Integrated Gene Expression Analysis of Controls Across Datasets Available of the Genes Implicated in Type 2 Diabetes Mellitus Complications

Integrated Gene Expression Analysis of Controls Across Datasets Available of The Genes Implicated In Type 2 Diabetes Mellitus Complications

Thesis Submitted for Partial Fulfillment of the Master of Technology in Computational Biology

By- Richa Rashmi

MT15131

Supervised by- Dr. S Ramachandran CSIR- Institute of Genomics and Integrative Biology

Acknowledgement With an overwhelming sense of pride and genuine obligation, I express my deepest regards to my supervisor Dr. Srinivasan Ramachandran. He explored my research compatibility and provided his valuable guidance throughout my work. He made me understand biological concepts, which was an unknown territory for me. He explored and nurtured my statistical knowledge. Without his perspicuous comments, suggestions and erudite guidance, I would not be able to accomplish this work. His patience to go through the draft is meticulously incredible. He has helped me a lot to improve my presentation and scientific writing skill through he comments and suggestions on this thesis. I would also like to acknowledge Director of our Institute for motivating and providing us the best facilities for studies. The faculty of Centre of Computational Biology have been very supportive and helped me whenever I approached them with a problem. The love and support given by all the lab members from CSIR-IGIB have been a great source of strength. They were always there to clear my smallest doubts and answer my queries promptly. I would also like to thank my batch mates from IIIT Delhi for their help and positive support.

The IIIT Delhi and CSIR-IGIB staff has been most cooperative and have been very helpful during past two years. A million thanks to my family for being very supportive and giving freedom to pursue the M.Tech. in Computational Biology. They have always encouraged me and given opportunity to fulfil my dreams. Above all I am very grateful to almighty God who brought me to this educational platform.

Contents

1. Introduction 1.1. Signs and symptoms 1.2. Complications 1.3. Causes of development of type 2 diabetes 1.4. Medical conditions 1.5. Pathophysiology 1.6. Diagnosis 1.7. Prevention 1.8. Management 1.9. Lifestyle 1.10. Genetic causes of diabetes mellitus type 2 1.10.1. Diabetes Genetic Factors in Type 2 Diabetes all factors in detail 1.10.2. The Sulfonylurea Receptor (ABCC8) 1.10.3. The Calpain 10 Enzyme (CAPN10) 1.10.4. The Glucagon Receptor (GCGR) 1.10.5. Gly40Ser mutation 1.10.6. The Enzyme Glucosidase (GCK) 1.10.7. The Glucose Transporter GLUT2 1.10.8. The Transcription Factor HNF4A 1.10.9. The Insulin Hormone (INS)

2. Materials and Methods 2.1. Data collection 2.1.1. Gene Expression Omnibus 2.1.2. T2DiACoD 2.2. Cross Platform Normalization 2.2.1. Loading and storage of raw data 2.2.2. Transformations of raw data 2.2.3. Annotation of raw data 2.2.4. Collapsing of redundant probe sets 2.2.5. Removal of batch effects and merging datasets 2.2.6. COMBAT for batch effect removal 2.3. Filtering dataset for Type 2 Diabetes and getting the normal range 2.3.1. Confidence interval

3. T2DiGER –Type 2 diabetes Gene Expression Report 3.1. T2DiGER User Interface 3.2. T2DiGER User Input 3.3. T2DiGER Background Operation 3.1 Generating Gene Expression Report 3.1 Quantile Normalization 3.1 Matching Probe Ids to Gene Names 3.4. T2DiGER output

4. Results 4.1. Evaluation of normalized datasets for tissue wise normal samples 4.2. Tissue tables 5. Summary and Conclusion Appendix Bibliography

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List of Figures

1.1. Scheme of the steps performed for cross platform normalization. 3.1. User input for function 1 3.2. User input for function 2 4.1. Boxplot to show comparison of raw and LS transformed samples from pancreas 4.2. Boxplot to show comparison of raw and LS transformed samples from heart 4.3. Boxplot to show comparison of raw and LS transformed samples from blood 4.4. Boxplot to show comparison of raw and LS transformed samples from muscle 4.5. Boxplot to show comparison of raw and LS transformed samples from adipose 4.6. Boxplot to show comparison of raw and LS transformed samples from liver 4.7. Bar graph showing gene expression values of control samples from liver tissue after batch effect removal. 4.8. Bar graph showing gene expression values of control samples from blood tissue after batch effect removal. 4.9. Bar graph showing gene expression values of control samples from heart tissue after batch effect removal. 4.10. Bar graph showing gene expression values of control samples from liver tissue after batch effect removal. 4.11. Bar graph showing gene expression values of control samples from muscle tissue after batch effect removal. 4.12. Bar graph showing gene expression values of control samples from pancreatic tissue after batch effect removal.

List of Tables

2.1. Details of datasets collected 2.2. Annotation files for the datasets collected A.1 Table for adipose tissue A.2 Table for blood tissue A.3 Table for heart tissue A.4 Table for liver tissue A.5 Table for muscle tissue A.6 Table for pancreas tissue

Chapter – 1

Introduction

India is the Diabetes capital of the world. 1As per a recent study approximately11 % of Indians may be victims. It may even be more as many cases go untested.2 Type 2 Diabetes mellitus is a chronic metabolic disease that is described by high glucose, insulin resistance, and the relative absence of insulin. Normal manifestations incorporate expanded thirst, frequent urination, and weight reduction. Side effects may likewise incorporate more craving, tiredness, and injuries that do not heal. Often symptoms come on slowly. Long term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycaemic state may happen however, ketoacidosis is remarkable. Diabetes Mellitus type 2 is majorly because of obesity and insufficient exercise in individuals who are hereditarily inclined. It makes up around 90% of instances of diabetes, with the other 10% due principally to Type 1 diabetes mellitus and gestational diabetes. In the case of Type 1 diabetes mellitus, there is an absence of insulin because of the breakdown of islet cells in the pancreas. The diagnosis of diabetes is by blood tests, for example, fasting plasma glucose, oral glucose resilience test, or A1C. Diabetes Mellitus type 2 can be prevented by maintaining a healthy weight, regular exercise, and eating appropriately. Treatment includes exercise and dietary changes. In the event that glucose levels are not satisfactorily brought down, the drug metformin is often prescribed. Many individuals may in the end likewise require insulin injections. A routine check of glucose levels is prescribed for those on insulin. This may not be required in those taking pills. Bariatric surgery frequently enhances diabetes in the individuals who are obese. 3Rates of Type 2 diabetes Mellitus have increased since 1960 in parallel with obesity. Starting at 2013, there were roughly 368 million individuals determined to have the ailment contrasted with around 30 million of every 1985. Generally, it happens in middle or old age.

1.1 Signs and symptoms

The 4most important symptoms of Type 2 diabetes mellitus are polyuria, polydipsia, polyphagia, and reduced weight. Moreover, obscured vision, irritation, fringe neuropathy, intermittent vaginal contaminations, and weakness are some of the symptoms that are normally present in individuals with Type 2 diabetes mellitus. Many individuals have no manifestations amid an initial couple of years and are diagnosed on routine testing. Individuals with Type 2 diabetes mellitus may seldom give the hyperosmolar hyperglycaemic express (a state of high glucose related with a diminished level of awareness and low blood pressure).

1.2 Complications

Diabetes Mellitus Type 2 is a chronic ailment resulting to a ten-year reduced life expectancy. Partly this is because of various complexities with which it is related, including 5 the increased risk of the cardiovascular diseases, including ischemic coronary illness and stroke; 20 times increased the risk of lower limb amputations, and

1 increased rates of hospitalizations. Diabetes Mellitus Type 2 is the biggest reason for kidney failure and visual impairments. Moreover, it has been related to the risk of vascular dementia, dementia because of Alzheimer's disease and cognitive dysfunction. 6Complications such as acanthosis nigricans, sexual dysfunction, and frequent infections are also related to Type 2 Diabetes Mellitus.

Hence the focus of this study is to devise a tool to detect if patients of Diabetes are at risk of developing complications. In addition, the tool can also predict if a normal individual without Diabetes is at risk of developing complications if at a later stage he/she develops Diabetes, prompting them to adopt healthy life style measures so that they either do not suffer from Diabetes later or at least delay its onset. 1.3 Causes of development of type 2 diabetes

The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. While some of these factors are under personal control, such as diet and obesity, other factors are not, such as increasing age, female gender, and genetics. A lack of sleep has been linked to type 2 diabetes. 7This is believed to act through its effect on metabolism. The nutritional status of a mother during fetal development may also play a role, with one proposed mechanism being that of altered DNA methylation. Various life factors are known to be vital to the advancement of T2DM, including being overweight (characterized by a body mass index of more prominent than 25), the absence of physical movement, horrible eating routine, stress, and smoking additionally seems to build the danger of type 2 diabetes mellitus. Dietary factors additionally impact the danger of creating type 2 diabetes mellitus. Utilization of sugary sweetened beverages in overabundance is related with an expanded hazard. The kind of fats in the eating routine is likewise essential, with soaked fats and trans unsaturated fats expanding the hazard, and polyunsaturated and monounsaturated fat diminishing the hazard. Eating bunches of white rice appears to likewise assume a part in expanding hazard. An absence of activity is accepted to cause 7% of cases. Persistent organic pollutants may also play a role. Most cases of diabetes involve many genes, with each being a small contributor to an increased probability of becoming a type 2 diabetic. If one identical twin has diabetes, the chance of the other developing diabetes within his lifetime is greater than 90%, while the rate for non-identical siblings is 25–50%. 8As of 2011, more than 36 genes had been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total heritable component of the disease. The TCF7L2 allele, for example, increases the risk of developing diabetes by 1.5 times and is the greatest risk of the common genetic variants. 8Most of the genes linked to diabetes are involved in beta cell functions There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes or "other specific types of diabetes"). These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson Mendenhall syndrome, among others. Maturity onset diabetes of the young constitutes 1–5% of all cases of diabetes in young people.

1.4 Medical conditions

There are a number of medications and other health problems that can predispose to diabetes. 9Some of the medications include glucocorticoids, thiazides, beta blockers, atypical antipsychotics, and statins. Those who have previously had gestational diabetes

2 are at a higher risk of developing type 2 diabetes. 10Other health problems that are associated include acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma, and certain cancers such as glucagonoma. Testosterone deficiency is also associated with type 2 diabetes.

1.5 Pathophysiology

Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance.11Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue. In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood. The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion. Other potentially 12important mechanisms associated with type 2 diabetes and insulin resistance include increased the breakdown of lipids within fat cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate regulation of metabolism by the central nervous system. However, not all people with insulin resistance develop diabetes, since an impairment of insulin secretion by pancreatic beta cells is also required.

1.6 Diagnosis

The 6World Health Organization definition of diabetes (both type 1 and type 2) is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either with a glucose tolerance test, 13two hours after the oral dose of plasma glucose ≥ 11.1 mmol/l (200 mg/dl). A random blood sugar of greater than 11.1 mmol/l (200 mg/dL) in association with typical symptoms or a glycated haemoglobin (HbA1c) of ≥ 48 mmol/mol (≥ 6.5 DCCT %) is another method of diagnosing diabetes The World Health Organization recommends testing those groups at high risk. High-risk groups include those over 45 year’s old; Those with a first degree relative with diabetes; Some ethnic groups, including Indians, Hispanics, African Americans, Native Americans, history of gestational diabetes and cases of polycystic ovary disease.

1.7 Prevention

The onset of type 2 diabetes can be delayed or prevented through proper nutrition and regular exercise. Intensive lifestyle measures may reduce the risk by over half.14 The benefit of exercise occurs regardless of the person's initial weight or subsequent weight loss. Evidence for the benefit of dietary changes alone, however, is limited with some evidence for a diet high in green leafy vegetables and some for limiting the intake of sugary drinks in those with impaired glucose tolerance, diet and exercise either alone or in combination with metformin or acarbose may decrease the risk of developing diabetes Lifestyle interventions are more effective than metformin. While low vitamin D levels are associated with an increased risk of diabetes, correcting the levels by supplementing vitamin D3 does not improve that risk.

1.8 Management

Management of type 2 diabetes focuses on lifestyle interventions, lowering other cardiovascular risk factors, and maintaining blood glucose levels in the normal range. Self-monitoring of blood glucose for people with newly diagnosed type 2 diabetes may be used in combination with education; however, the benefit of self-monitoring in that not using multi dose insulin is questionable. In those who do not want to measure blood levels, measuring urine levels may be done. Managing other cardiovascular risk factors, such as hypertension, high cholesterol, and microalbuminuria improves a person's life expectancy. Decreasing the systolic blood pressure to less than 140 mmHg is associated with a lower risk of death and better outcomes. Intensive blood pressure management (less than 130/80 mmHg) as opposed to standard blood pressuee management (less than 140/85–100 mmHg) results in a slight decrease in stroke risk but no effect on overall risk of death. 1516Intensive blood sugar lowering (HbA1c<6%) as opposed to standard blood sugar lowering (HbA1c of 7–7.9%) does not appear to change mortality. The goal of treatment is typically an HbA1c of around 6.4% or a fasting glucose of less than 7.2 mmol/L (130 mg/dL); However these goals may be changed after professional clinical consultation, taking into account particular risks of 17hypoglycaemia and life expectancy. It is recommended that all people with type 2 diabetes get regular ophthalmology examination. Treating gum disease in those with diabetes may result in a small improvement in blood sugar levels.

1.9 Lifestyle

A proper diet and exercise are the foundations of diabetic care, with a greater amount of exercise yielding better results. Aerobic exercise leads to a decrease in HbA1c and improved insulin sensitivity.14 Resistance training is also useful and the combination of both types of exercise may be most effective. A diabetic diet that promotes weight loss is important. While the best diet type to achieve this is controversial, 18a low glycemic index diet or low carbohydrate diet has been found to be effective.

1.10 Genetic causes of diabetes mellitus type 2

Most cases of diabetes mellitus type 2 involved many genes contributing small amount to the overall condition. 19As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease. There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes). These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson-Mendenhall syndrome, among others. Maturity onset diabetes of the young constitutes 1–5% of all cases of diabetes in young people. Genetic cause and mechanism of type 2 diabetes is largely unknown. However, single nucleotide polymorphism (SNP) is one of many mechanisms that lead to increased risk for type 2 diabetes. To locate genes and loci that are responsible for the risk of type 2 diabetes, genome wide association studies (GWAS) was utilized to compare the genomes of diabetic patient group and he nondiabetic control group. 20The diabetic patients’ genome sequences differ from the controls’ genome in specific loci along and around numerous genes, and these differences in the nucleotide sequences alter phenotypic traits that exhibit increased susceptibility to the diabetes. GWAS has

4 revealed 65 different loci (where single nucleotide sequences differ from the patient and control group’s genomes), and genes associated with type 2 diabetes, including TCF7L2, PPARG, FTO, KCNJ11,NOTCH2, WFS1, IGF2BP2, SLC30A8, JAZF1, HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PARG6, ZBED3, SLC30A8, CDKAL1, GLIS3, GCKR, among others.KCNJ11 (potassium inwardly rectifying channel, subfamily Member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. 720In addition there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. However, this is not a comprehensive list of genes that affects the proneness to the diabetes. Most SNPs that increase the risk of diabetes reside in noncoding regions of the genes, making the SNP’s mechanism for increasing susceptibility largely unknown. However, they are thought to influence the susceptibility by altering the regulation of those gene expressions. Only few genes (PARG6, KCNJ11-ABCC8, SLC30A8, and GCKR) have SNPs in the open reading frame (ORF). 20These SNPs in ORFs result in altering of the protein function, and the altered function and therefore compromise the performances of the protein product causes increased susceptibility to the type 2 diabetes. One of the examples of gene regulation in non-ORF SNPs that influences susceptibility is the changes in nucleotide sequence in microRNA (miRNA) binding site. miRNAs regulate gene expression by binding to the target mRNAs and physically block translation. SNPs on the miRNA-binding site can result in faulty levels of gene expression as miRNA fails to bind to the corresponding mRNA effectively, leading to excess amount of protein product overall. Although the protein structures of the genes with SNPs are identical to that of the normal gene product, due to their faulty level of expressions, those genes increase risk. Genes such as CDKN2A, CDKN2B, and HNF1B exhibit increase the risk phenotype with SNPs in their 3' UTR miRNA binding sites. As CDKN2A and B regulate the pancreatic beta-cell replication, and HNF1B is homeodomain containing transcription factor that regulates other genes, faulty regulations of those genes increase the risk of diabetes. Another example of faulty gene regulation that influences the susceptibility is the SNPs in promoter regions of the genes. Gene like APOM and APM1 increase the risk of type 2 diabetes when there are SNPs in their proximal promoter regions. Promoters are sequences of DNA that allows proteins such as transcription factors to bind for gene expression, and when the sequences are modified, the proteins no longer bind as effectively, resulting in depressed level of gene expression. 21APOM is partly responsible for producing pre beta-high-density lipoprotein and cholesterol, and 22APM1 is responsible for regulating glucose level in blood and fatty acid. Decreasing the level these gene products reduce the body’s ability to handle glucose, which leads to the increased risk of diabetes. It is important to note that those discovered genes do not determine susceptibility to diabetes for all people or cases. As the risk of diabetes is combination of the gene regulations and the interplay between those gene products, certain genes may not pose a threat to increase the susceptibility. 23TCF7L2 is one of the well-studied genes for diabetes susceptibility in most populations. Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich’s ataxia. Wolfram’s syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym 24DIDMOAD. While obesity is an independent risk factor for type 2 diabetes that may be linked to lifestyle, obesity is also a trait that may be strongly inherited. Other research also shows that type

2 diabetes can cause obesity as an effect of the changes in metabolism and other deranged cell behaviour attendant on insulin resistance. However, 25environmental factors (almost certainly diet and weight) play a large part in the development of type 2 diabetes in addition to any genetic component. Genetic risk for type 2 diabetes changes as humans first began migrating around the world, implying a strong environmental component has affected the genetic-basis of type 2 diabetes. This can be seen from the adoption of the type 2 diabetes epidemiological pattern in those who have moved to a different environment as compared to the same genetic pool who have not. Immigrants to Western developed countries, for instance from India, may be more prone to diabetes as compared to its lower incidence in their countries of origins. Such developments can also be found in environments which have had a recent increase in social wealth, increasingly common throughout Asia.

1.10 .1 Diabetes Genetic Factors in Type 2 Diabetes all factors in detail

Type 2 diabetes has been loosely defined as "adult onset" diabetes, although as diabetes becomes more common throughout the world, cases of type 2 diabetes are being observed in younger people. It is increasingly common in children. In determining the risk of developing diabetes, environmental factors such as food intake and exercise play an important role. The majority of individuals with type 2 diabetes are either overweight or obese. Inherited factors are also important, but the genes involved remain poorly defined. In rare forms of diabetes, mutations of one gene can result in disease. However, in type 2 diabetes, many genes are thought to be involved. "Diabetes genes" may show only a subtle variation in the gene sequence, and these variations may be extremely common. 26The difficulty lies in linking such common gene variations, known as single nucleotide polymorphisms (SNPs), with an increased risk of developing diabetes. One method of finding the diabetes susceptibility genes is by whole-genome linkage studies. The entire genome of affected family members is scanned, and the families are followed over several generations and/or large numbers of affected sibling-pairs are studied. Associations between parts of the genome and the risk of developing diabetes are looked for. To date only two genes, calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A), have been identified by this method.

1.10.2 The Sulfonylurea Receptor (ABCC8)

27Sulfonylureas are a class of drugs used to lower blood glucose in the treatment of type 2 diabetes. These drugs interact with the sulfonylurea receptor of pancreatic beta cells and stimulate insulin release. The sulfonylurea receptor is encoded by the ABCC8 gene, and genetic variation of ABCC8 may impair the release of insulin. The protein encoded by the ABCC8 gene is a member of the ATP-binding cassette transporters. These proteins use energy in the form of ATP to drive the transport of various molecules across cell membranes. ABCC8 belongs to a subfamily of transporters that contains the chloride channel that is mutated in cystic fibrosis (CFTR) and also the proteins that are involved in multi-drug resistance. The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene. KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin. The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in

6 the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels. The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins. Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion; a condition termed familial persistent hyperinsulinemia hypoglycaemia of infancy (PHHI) (2-4). Genetic variation in ABCC8 has also been implicated in the impaired release of insulin that is seen in type 2 diabetes.

Molecular level gene expression

ABC genes are found in many different eukaryotic species and are highly conserved between species, indicating that many of these genes existed early in eukaryotic evolution. A BLAST search using human ABCC8 as a query finds proteins in 30 different species, which include multicellular organisms (metazoans), fungi, and plants. Potential true homologous genes have been identified in the mouse and rat. By fluorescence in situ hybridization, it was found that the ABCC8 gene maps to the short arm of chromosome 11. It has 41 exons (coding regions) that span over 84,000 bases. ABCC8 maps to chromosome 11, between approximately 17,370–17,470 kilobases (kb). The ABC transporter proteins, such as ABCC8, typically contain two ATP-binding domains and two transmembrane domains. The ATP-binding domains are also known as nucleotide binding folds (NBFs), and mutations in either NBF1 or NBF2 can lead to PHHI (6). This suggests that both NBF regions of the SUR are needed for the normal regulation of KATP channel activity. As found in all proteins that bind ATP, the nucleotide binding domains of the ABC family of proteins contain characteristic motifs called Walker A and B. The Walker A motif contains a lysine residue that is critical for activating the KATP channel. When this lysine residue is mutated in NBF1, but not NBF2, the KATP channel can no longer be activated. In addition, ABC genes also contain a signature C motif. The transmembrane domains contain 6–11 membrane spanning helices, and the ABCC protein contains 6. These helices provide the protein with specificity for the molecule they transport across the membrane. Several single nucleotide polymorphisms (SNPs have been found within the ABCC8 gene. Usually SNPs linked with disease occur within the coding regions (exons) of the genes, and they result in a non-synonymous amino acid change. In ABCC8, there are seven such SNPs (at the time of writing) that cause a switch of amino acids in the mature protein. However, one of the SNPs of the ABCC8 gene that has been linked with diabetes (R1273R) does not cause an amino acid change. The two genes that encode the KATP channel, ABBC8 and KCNJ11, reside adjacent to one another on chromosome 11. A variant of ABCC8, called A1369S, is in almost complete linkage disequilibrium with a variant of KCNJ11 called E23K. This means that from the genetic evidence, it is difficult to determine whether it is the A1369S variant or the E23K variant that predisposes to type 2 diabetes. The switch of glutamate to lysine at residue 1506 (E1506K) in the SUR1 protein caused a congenital hyperinsulinemia. The mutation reduced the activity of KATP channels, increasing insulin secretion. By early adulthood, the ability of the beta cells to secrete adequate amounts of insulin was exhausted, leading to diabetes. A silent variant in exon 31 of the ABCC8 gene has been associated with high concentrations of insulin in non-diabetic Mexican Americans. The codon AGG is mutated to AGA, but these still codes for the residue arginine (R1273R).

The normal and mutant alleles were called G and A, respectively. Among non- diabetics, those who were homozygous for the mutant allele (AA genotype) had higher levels of insulin when fasting, compared with heterozygotes (AG) and normal wildtype (GG). Individuals with the AA genotype are at a higher risk of diabetes because of an over-secretion of insulin. Two common polymorphisms of the ABCC8 gene (exon 16-3t/c and exon 18 T/C) have been variably associated with type 2 diabetes. However, a recent large case control study in Britain revealed that these ABCC8 variants did not appear to be associated with diabetes.

1.10.3 The Calpain 10 Enzyme (CAPN10)

27Calpain 10 is a calcium-activated enzyme that breaks down proteins. Variation in the non-coding region of the CAPN10 gene is associated with a threefold increased risk of type 2 diabetes in Mexican Americans. A genetic variant of CAPN10 may alter insulin secretion, insulin action, and the production of glucose by the liver. The discovery of CAPN10 marks the first time that screening the entire genome led to the identification of a gene linked to a common and genetically complex disease such as type 2 diabetes. In 1996, a link was made between a region of chromosome 2 and an increased risk of diabetes in Mexican Americans in Texas, USA. The region on the chromosome, located near the end of the long arm of chromosome 2, was named NIDDM1 (Non-Insulin- Dependent Diabetes Mellitus 1). To pinpoint a gene that conferred risk, new statistical techniques were used, and the region was sequenced in greater and greater detail. Four years later, a new diabetes susceptibility gene, CAPN10, was discovered. The new gene encoded the enzyme calpain 10, a member of the calpain family of cysteine proteases. These enzymes are activated by calcium and regulate the functions of other proteins by cleaving pieces off, leaving the altered protein either more or less active. In this way, they regulate biochemical pathways and are involved in intracellular signalling pathways, cell proliferation, and differentiation. Calpains are found in all human cells, and 14 members of the calpain family are now known, many of which are associated with human disease. Calpains 1 and 2 are implicated in causing injury to the brain after a stroke and also have been linked to the pathology seen in Alzheimer's disease. Calpain 3 is mainly found in the muscle, and mutations cause limb-girdle muscular dystrophy. Mutations of calpains in the worm Caenorhabditis elegans affect sexual development, and mutations of a calpain-like gene in the fly cause a degeneration of parts of the nervous system. Calpain 10 was an unexpected find in the search for a putative diabetes susceptibility gene. Its link with diabetes is complex; susceptibility is not attributable to a single variation but to several variations of DNA that interact to either increase, decrease, or have no effect on the risk of developing diabetes. Calpain 10 is an atypical member of the calpain family, and its biological role is unknown. Because CAPN10 mRNA is expressed in the pancreas, muscle, and liver, its role in diabetes may involve insulin secretion, insulin action, and the production of glucose by the liver.

Molecular level gene expression Calpains are found in all human cells and are found throughout the animal kingdom. A BLAST using human CAPN10 as a query finds proteins in 18 different species, all of which are multicellular organisms (metazoans). However, potential true homologous genes have been identified only in the mouse. The calpains consist of a large catalytic subunit and a small regulatory subunit. The large subunit contains four domains (I–IV), and the catalytic center of the cysteine protease is located in domain II. Domain I is the

N-terminal domain that is processed when the enzyme is activated, domain III is a linker domain, and the C-terminal domain IV binds calcium and resembles the calcium- binding protein, calmodulin. Domain IV also has characteristic EF-hand motifs. Calpain 10 is an atypical calpain in that it lacks the calmodulin-like domain IV and instead has a divergent C-terminal domain, domain T. Calpains 5 and 6 also have a domain T, and together they form a subfamily of calpains (6). The CAPN10 gene maps to chromosome 2. It has 13 exons (coding regions) that span about 30,000 bases.Alternate splicing of the gene creates at least eight transcripts (named isoform a through isoform h), which in turn encode proteins ranging from 138 to 672 amino acids in length. CAPN10 maps to chromosome 2, between approximately 241,840–241,880 kilobases (kb). However, the SNPs of the CAPN10 gene that have been linked with diabetes are located in introns (introns 3, 6, and 19), and because introns are not transcribed, they do not directly cause an amino acid change. Instead, it is proposed that SNPs in CAPN10 introns may alter risk by affecting the transcriptional regulation of calpain 10.

1.10.4 The Glucagon Receptor (GCGR)

27Glucagon is a key hormone in the regulation of glucose levels. As such, the GCGR gene which encodes its receptor is a candidate diabetes susceptibility gene. A mutant glucagon receptor has been associated with diabetes. Glucagon, like insulin, is a peptide hormone that is secreted by the pancreas. Unlike insulin, glucagon acts to promote the mobilization of fuels, particularly glucose. The glucagon receptor is a member of the 7- transmembrane receptor (7TM) family. These receptors have also been called the Serpentine receptors because of the way the single polypeptide chain of the receptor "snakes" back and forth across the cell membrane. This diverse family of receptors not only responds to hormones such as glucagon but also transmits many other signals including light, smell, and neurotransmitters. When glucagon outside of the cell binds to the glucagon receptor, it induces a conformational change in the receptor that can be detected inside the cell. The activated receptor stimulates intracellular cAMP production, which in turn stimulates protein kinase A (PKA) to phosphorylate many target proteins, including two enzymes that lead to the breakdown of glycogen and inhibit further glycogen synthesis.

Molecular level gene expression

The GCGR gene maps to chromosome 17 It has 14 exons (coding regions) that span around 10,700 bases The 7TM receptor encoded by this gene is also known as a G protein coupled receptor because a G protein (guanylnucleotide-binding protein) conveys an intermediate step in signal transduction. In the inactivated state, the G protein coupled to the glucagon receptor exists as a heterodimer consisting of α, , and subunits. The α subunit (Gα) binds GDP. Many different G proteins exist, and for the glucagon receptor, because the activated Gα subunit stimulates adenylate cyclase, the receptor is classified as a Gαs receptor ("s" for stimulatory effect of the subunit). A BLAST search using human GCGR as a query finds proteins in 35 different species, which are all metazoans (multicellular organisms). However, potential true homologous genes have thus far been identified only in the mouse, rat, and fruit fly.

1.10.5 Gly40Ser mutation

27A Gly40Ser mutation of the receptor gene was linked with type 2 diabetes in French and Sardinian patients. The mutation occurs in exon 2 and disrupts an extracellular region of the receptor when the signalling properties of the Gly40Ser mutant receptor were examined; it was found that the mutant receptor bound glucagon with a threefold lower affinity compared with the wildtype receptor. In addition, the production of cAMP in response to glucagon was decreased, and glucagon-stimulated insulin secretion was also decreased. Decreased insulin secretion was observed in Gly40Ser carriers in a Brazilian population, but the mutant receptor was not associated with type 2 diabetes.

1.10.6 The Enzyme Glucosidase (GCK)

27Glucokinase, encoded by the GCK gene speeds up glucose metabolism and acts as a "glucose sensor" in the beta cell. Mutant glucokinase causes a rare form of diabetes and may also play a role in type 2 diabetes. The enzyme glucokinase catalyzes glucose metabolism in the liver and in the pancreatic beta cell. Glucokinase traps glucose inside the cell by catalyzing its phosphorylation to produce glucose-6-phosphate. This is the first and rate-limiting step in glycosis, a pathway that produces energy in the form of ATP from glucose. Glucokinase (also called hexokinase IV) differs from the other hexokinases that are found in other tissues. First, glucokinase has a lower affinity for glucose. This allows other organs such as the brain and muscles to have first call on glucose when their supply is limited. One other highlight is that is that glucokinase is not hindered by its item, glucose-6-phosphate. This lack of negative feedback inhibition enables hepatic glucokinase to remain active while glucose is abundant, ensuring that the liver can continue removing glucose from the blood ensuring that no glucose goes to waste. Glucokinase is proposed to be an important "glucose sensor" in the following way. The rate of glucose metabolism is determined by the rate of glucose phosphorylation, which is catalyzed by glucokinase in the liver and pancreas. The liver and pancreas also express glucose transporter-2 (GLUT2), an insulin-independent cellular protein that mediates the transport of glucose into cells. The capacity of GLUT2 to transport glucose is very high, facilitating rapid equilibrium between extracellular and intracellular glucose. Thus, in effect, the extracellular glucose concentrations are sensed by glucokinase. By catalyzing the rate-limiting step of glucose metabolism in the liver, glucokinase enables the liver to buffer the rise in glucose that takes place after a meal. In the pancreas, glucokinase is the glucose sensor for insulin release. The threshold for glucose-stimulated insulin release is about 5 mmol/l. Mutations of GCK that alter this threshold manifest as three different syndromes and highlight the importance of GCK in glucose homeostasis and diabetes. Activating mutations lower the beta cell threshold for insulin release to as low as 1.5 mmol/l of glucose, leading to an increase in insulin release. This manifests as persistent hyperinsulinemia hypoglycaemia of infancy (PHHI). Inactivating mutations raise the beta cell threshold for insulin release. If two alleles altered by inactivating mutations are inherited, the level of glucose needed to stimulate insulin release from the pancreas is extremely high. Because of its role as a glucose sensor, GCK is a candidate susceptibility gene for type 2 diabetes.

Molecular level gene expression

The hexokinase family consists of several enzymes that are all evolutionarily related. In vertebrates, there are four hexokinases named I to IV. Glucokinase is a distinct member of this family. A BLAST search using human GCK as a query finds proteins in 46 different species, which range from metazoan (multicellular organisms), fungi, plants, and other eukaryotes. Potential true homologous genes have thus far been identified in the mouse, rat, fly, mosquito, nematode worm, and the plant, mouse-ear cress. The GCK gene maps to chromosome 7. It has 12 exons (coding regions) that span around 46,000 bases . There are three GCK transcript variants that differ in their first exon, and their expression is tissue specific. One isoform predominates in the pancreatic beta cells; the other two isoforms are found in the liver. The glucokinase enzyme is found in the outer membrane compartment of mitochondria in these tissues. GCK maps to chromosome 7, between approximately 43,000–44,000 kilobases (kb)

1.10.7 The Glucose Transporter GLUT2

27The GLUT2 gene encodes a glucose transporter which regulates the entry of glucose into pancreatic beta cells and is thought to be a "glucose sensor". Mutations of GLUT2 cause a rare genetic syndrome that disrupts blood glucose regulation. Common variants of GLUT2 may be linked with type 2 diabetes.

1.10.8 The Transcription Factor HNF4A

27The HNF4A gene encodes a transcription factor that is found in the liver and pancreas. Because HNF4A maps to a region of chromosome 20 that is linked with type 2 diabetes and because mutations of this gene cause a rare form of autosomal dominant diabetes, the HNF4A gene is considered to be a strong candidate for involvement in type 2 diabetes. The expression of a wide range of genes in the liver is regulated by the transcription factor HNF4A (hepatocyte nuclear factor 4 alpha). Many functions that the liver carries out may appear and disappear, depending on whether HNF4A is expressed. In addition, HNF4A controls the expression of another transcription factor; hepatocyte nuclear factor 1α (HNF1A), which in turn regulates the expression of several important genes in the liver. As the name suggests, hepatocyte nuclear factor 4 is found in abundance in the liver, but it is also found in the beta cells of the pancreas, the kidneys, and intestines. Together with other transcription factors such as HNF1A and HNF1B (encoded by TCF1 and TCF2, respectively), they make up part of a network of transcription factors that function together to control gene expression in the developing embryo. In particular, HNF4A is thought to play an important role in the development of the liver, kidney, and intestines. In pancreatic beta cells, this network of transcription factors regulates the expression of the insulin gene. In addition, HNF4 and HNF1 regulate the expression of several other genes linked with insulin secretion, e.g., genes that encode proteins involved in glucose transport and glucose metabolism. Mutations of HNF4A can cause an extremely rare form of diabetes, maturity onset diabetes in the young (MODY). Whereas type 2 diabetes is a disorder usually of late onset with significant genetic basis, MODY by definition occurs in the young (onset at age less than 25 years) and is inherited in an autosomal dominant fashion.

Molecular level gene expression

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. HNF4A is an orphan receptor; the ligand(s) that binds to this receptor is unknown. A BLAST search using human HNF4A as a query finds proteins in 47 different species, which are all multicellular species (metazoans). The HNF4A gene maps to chromosome 20. It has 11 exons (coding regions) that span over 30,000 bases. There are at least three different transcript variants of this gene, which encode three different protein isoforms (a, b, and c). The longest mRNA transcript, NM_000457, encodes the longest HNF4A protein (isoform b), Containing over 450 amino acids. Several single nucleotide polymorphisms. At the time of writing, three non- synonymous amino acid changes caused by SNPs have been observed in the longest protein isoform (isoform b). At present, none of these SNPs have been associated with either type 2 diabetes or MODY (see known allelic variants). However, several SNPs upstream of the coding region have been associated.

1.10.9 The Insulin Hormone (INS)

27 The INS gene encodes the precursor to the hormone insulin. Genetic variations of the insulin gene (variable number tandem repeats and SNPs) may play a role in susceptibility to type 1 and type 2 diabetes. Insulin is a hormone that has a wide range of effects on metabolism. Its overall action is to encourage the body to store energy rather than use it, e.g., insulin favours the storage of glucose as glycogen or fat as opposed to breaking down glucose to release ATP. For a summary of the actions of insulin, see the Physiology and Biochemistry of Sugar Regulation. Insulin is composed of two distinct polypeptide chains, chain A and chain B, which are linked by disulfide bonds. Many proteins that contain subunits, such as haemoglobin, are the products of several genes. However, insulin is the product of one gene; INS. INS actually encodes an inactive precursor called preproinsulin. Preproinsulin is processed into proinsulin by removal of a signalling peptide; however, proinsulin is also inactive. The final processing step involves removal of a C-peptide (a connecting peptide that links chain A to chain B), and this process produces the mature and active form of insulin. Several single nucleotide polymorphisms (SNPs ) have been found within the INS gene, none (at the time of writing) of which cause non-synonymous amino acid changes in the mature protein A BLAST search using the human proinsulin precursor as a query finds proteins in 107 different species, which are all metazoans apart from three plants and one bacterium. However, potential true homologous genes have thus far been identified only in the mouse and rat.

1.11 Objectives

Advances in microarray technology have reached a stage where it is possible to "watch" simultaneously the activation state of all the genes of a given biological entity under a variety of external stimuli (drugs, diseases, toxins etc). The analysis of the gene expression data complements the better-known analysis of the individual variations in the genetic code. In this project gene expression analysis has been used to find the range of expression of genes that implicate complications in case of a healthy individual. This analysis has

12 been done tissue wise. T2DiGER is the web based tool which will help researchers and doctors to compare gene expression of patients to normal person and help the patients in taking necessary measures. There are two major objectives of this project 1. Tissue wise integration of gene expression data from different microarray platforms and calculate range of expression of genes that implicate complication in type 2 diabetes in case of a healthy person. 2. Implementation of a web based tool named T2DiGER which can compare gene expression data of a patient with the gene expression data of a healthy person and generate a detailed gene expression report.

Chapter 2

Materials and Methods In this chapter I explain the methodology I have employed in process of cross-platform normalization and creating a range of expression of gene that implicates complications in type two diabetes in healthy people. My methodology also includes the creation of a web application that can compare any person’s gene expression data to the normal gene expression in case of type 2 diabetes. The primary purpose of my methodology has been to allow user to compare their gene expression data to healthy controls and see what kind of complications they are likely to get.

2.1 Data collection Two types of datasets were required for the analysis- (a) The tissue wise gene expression data of healthy controls for type 2 diabetes (b) List of genes associated with complications in type 2 diabetes.

The tissue wise gene expression data of healthy controls for type 2 diabetes is collected from 28Gene Expression Omnibus and list of genes associated with complications in type 2 diabetes is collected from 29T2DiACOD. 2.1.1 Gene Expression Omnibus The Gene Expression Omnibus (GEO) is an international public repository that documents and unreservedly appropriates microarray, cutting edge sequencing, and different types of high-throughput useful genomic informational collections. Roughly 90% of the information in GEO are quality articulation considers that examine an expansive scope of organic subjects including malady, improvement, development, resistance, biology, toxicology, digestion, and that's just the beginning. The principle objectives of GEO are to: • Provide a flexible and robust essential information file database in which to productively store a wide assortment of high-throughput utilitarian genomic informational collections. • Offer basic accommodation methodology and organizations that help finish and very much clarified information stores from the examination group. • Provide easy to understand systems that enable clients to find, audit, and download studies and quality articulation profiles of intrigue. From GEO data was downloaded from 13 experiments from nine different platforms. Table 2.1 has details of all the samples. Table 1.1 Details of datasets collected

GSE ID Sample ID Tissue Type GSM228564 GSE9006 GSM228562 Blood GSM228565 GSM228563 GSM228566

GSM228567 GSM346581 GSM228568 GSM346584 GSM228569 GSM346585 GSM228570 GSE26887 GSM662158 GSM228571 GSM662159 GSM228572 GSM662160 GSM228573 GSM662161 GSM228574 GSM662162 GSM228575 GSE23343 GSM572800 Liver GSM228576 GSM572801 GSM228577 GSM572802 GSM228578 GSM572803 GSM228579 GSM572804 GSM228580 GSM572805 GSM228581 GSM572806 GSM228663 GSE8157 GSM201849 Muscle GSM228664 GSM201850 GSM228665 GSM201851 GSM228666 GSM201852 GSE39825 GSM979903 GSM201853 GSM979904 GSM201854 GSM979905 GSM201855 GSM979906 GSM201856 GSM979907 GSM201857 GSM979908 GSM201858 GSE54350 GSM1313608 Adipose GSM201859 GSM1313612 GSM201861 GSM1313613 GSM201862 GSM1313614 GSE12643 GSM317332 GSM1313615 GSM317333 GSM1313617 GSM317334 GSE16415 GSM412607 GSM317335 GSM412608 GSM317336 GSM412609 GSM317337 GSM412610 GSM317338 GSM412611 GSM317339 GSE13760 GSM346561 Heart GSM317340 GSM346566 GSM317341 GSM346568 GSE6798 GSM155631 GSM346570 GSM155643 GSM346573 GSM155644 GSM346575 GSM155729 GSM346576 GSM156170 GSM346578 GSM156171

GSM156176 GSM946724 GSM156177 GSM946725 GSM156178 GSM946726 GSM156179 GSM946727 GSM156180 GSM946728 GSM156181 GSM946729 GSM156184 GSM946730 GSE55650 GSM1341141 GSM946731 GSM1341142 GSM946732 GSM1341143 GSM946733 GSM1341144 GSM946734 GSM1341145 GSM946735 GSM1341146 GSM946736 GSM1341153 GSM946737 GSM1341154 GSM946738 GSM1341155 GSM946741 GSM1341156 GSM946742 GSM1341157 GSM946743 GSE38642 GSM946700 Pancreas GSM946744 GSM946701 GSM946748 GSM946702 GSM946749 GSM946703 GSM946750 GSM946704 GSM946751 GSM946705 GSM946752 GSM946706 GSM946753 GSM946707 GSM946754 GSM946708 GSM946755 GSM946709 GSM946756 GSM946712 GSM946757 GSM946713 GSM946758 GSM946714 GSM946759 GSM946715 GSM946762 GSM946716 GSE25724 GSM631755 GSM946717 GSM631756 GSM946718 GSM631757 GSM946719 GSM631758 GSM946720 GSM631759 GSM946721 GSM631760 GSM946722 GSM631761 GSM946723

2.1.2 T2DiACoD T2DiACoD is an online platform which gives curated and incorporated data about the qualities engaged with improvement and movement of Type 2 Diabetes Mellitus. This

16 database additionally gives data about the qualities and pathways with proving for the part in diabetes under hazard factors including corpulence, food habits, aggravation, stress and complex issue that are related with type 2 Diabetes Mellitus. These complex disorders incorporate atherosclerosis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, the cardiovascular malady which are observed to be generally related as a result of T2DM. The data gave in the database incorporates a la mode populace savvy investigation of different qualities, the SNPs approved tentatively, tissue particular quality articulation designs from microarray information, and miRNAs related with the infection pathogenesis. According to T2DiACoD there are total 650 genes that are likely to cause complications in type 2 diabetes. List of 650 genes are as follows: 1. ABCA1 43. FKBP2 85. PPARA 127. ATM 2. ABCG1 44. FMO3 86. PPARG 128. BNIP3 3. ACAT1 45. FMOD 87. PRCP 129. CD247 4. ADAM17 46. FOXA2 88. PRMT2 130. CD40LG 5. ADIPOQ 47. FOXO1 89. PTGDS 131. CD9 6. AGER 48. FPR1 90. PTX3 132. CDC123 7. ALB 49. GIP 91. RBP4 133. CDKAL1 8. ALOX5AP 50. GLO1 92. REN 134. CDKN2A 9. ANGPTL2 51. GPX1 93. RETN 135. CNDP1 10. APOA1 52. GSTM1 94. ROCK2 136. CST3 11. APOA5 53. GSTT1 95. SCAF1 137. CTSS 12. APOM 54. HGF 96. SCARB1 138. CYP2J2 13. APPL1 55. HP 97. SIRT1 139. CYP7A1 14. B2M 56. ICAM1 98. SOST 140. DDIT3 15. BAAT 57. IL18 99. STEAP4 141. DKK1 16. BMP2 58. IL6 100. TCF7L2 142. EBF1 17. CAPN10 59. INS 101. TIMP3 143. EGFR 18. CCL2 60. IRS2 102. TLR4 144. ENG 19. CCR2 61. LDLR 103. TNFRSF11B 145. ERBB2 20. CCR5 62. LEP 104. TRPC6 146. FABP1 21. CD163 63. LPA 105. TXN 147. FFAR2 22. CD36 64. LPL 106. TXNIP 148. FGF19 23. CD4 65. MAFB 107. UCP2 149. FKBP10 24. CD40 66. MIF 108. UTS2 150. FKBP4 25. CETP 67. MMP2 109. VCAM1 151. FKBP8 26. CHI3L1 68. MMP9 110. VEGFA 152. FTO 27. COG2 69. MOK 111. ABO 153. G6PD 28. CRK 70. MPO 112. ACE 154. GCKR 29. CRP 71. MTHFR 113. ACE2 155. GDF15 30. CX3CL1 72. NLRP3 114. ACVR1C 156. GGT1 31. CXCL5 73. NOS3 115. ADCY5 157. GHRL 32. CYBA 74. NOX4 116. ADIPOR1 158. GK 33. CYP1A1 75. NPY 117. AHSA1 159. GLP1R 34. DHCR7 76. NQO1 118. AHSG 160. GLUL 35. DPP4 77. PARP1 119. AKT1 161. GYS1 36. ELN 78. PCSK9 120. ALDH2 162. HHEX 37. ENTPD1 79. PDGFD 121. ALPK1 163. HIF1A 38. FABP4 80. PLA2G2A 122. APOB 164. HMGB1 39. FABP5 81. PLTP 123. APOC3 165. HNF1B 40. FGF21 82. PON1 124. APOE 166. HNF4A 41. FGF23 83. PON2 125. APOH 167. IGF1 42. FGFR1 84. PON3 126. APOL1 168. IL1B

169. JAZF1 225. ADH1B 281. CTGF 337. HLA-DQA1 170. MAP3K5 226. ADM 282. CX3CR1 338. HMCN1 171. MBL2 227. AGT 283. CXCL10 339. HMGA2 172. MBL3P 228. AGTR1 284. CXCL11 340. HMGCS2 173. MC4R 229. AKR1B1 285. CXCL12 341. HMOX1 174. MSH2 230. AKR1B10 286. CXCL16 342. HNF1A 175. MT1A 231. ALDH1A1 287. CXCL8 343. HPSE 176. MTHFD1L 232. ALPL 288. CXCL9 344. HSPA1A 177. NAGLU 233. AMBP 289. CYP24A1 345. HSPA1B 178. NAMPT 234. ANG 290. DCXR 346. HSPB1 179. NPPA 235. ANGPTL4 291. DDAH1 347. HSPG2 180. NPY2R 236. AOC2 292. DEFA1 348. HTR2A 181. NPY5R 237. APC 293. DES 349. HYOU1 182. NR3C2 238. APLNR 294. DGKH 350. ID1 183. NTS 239. APOC1 295. DNMT1 351. IFNG 184. NUCB2 240. AQP5 296. DSEL 352. IGF2 185. OXT 241. AR 297. EBF2 353. IGFBP1 186. PARL 242. ATF4 298. EDN1 354. IGFBP3 187. PEAR1 243. BAMBI 299. EDNRA 355. IL10 188. PGF 244. BASP1 300. EGF 356. IL17A 189. PHACTR1 245. BCL2 301. EIF2AK3 357. IL1RN 190. PLIN1 246. BMP4 302. EIF4EBP1 358. ILK 191. PLIN2 247. C5 303. ELMO1 359. ITGAM 192. PLN 248. CARM1 304. ENPP1 360. JAK2 193. POMC 249. CAT 305. EPO 361. KCNQ1 194. PPARGC1A 250. CAV1 306. EPOR 362. KL 195. PRDX1 251. CCK 307. ERBB4 363. KLF10 196. PRDX2 252. CCKAR 308. ERCC1 364. KLF6 197. PRDX4 253. CCL20 309. ERCC4 365. KMT2C 198. PRDX6 254. CCL5 310. ERRFI1 366. LAMC1 199. PSMA6 255. CCR1 311. ESAM 367. LAP3 200. PTGS2 256. CD2AP 312. ESR1 368. LIMK2 201. PTH 257. CD38 313. EXOSC7 369. LMNA 202. PTPN1 258. CD47 314. EZR 370. LTA 203. RNLS 259. CD63 315. F11 371. MAD2L2 204. S100A12 260. CD68 316. F2R 372. MALT1 205. SAA@ 261. CD69 317. FABP2 373. MAPK1 206. SETD7 262. CD74 318. FASN 374. MAPK14 207. SHBG 263. CD80 319. FN3K 375. MCAM 208. SLC2A1 264. CDH1 320. FOS 376. MEP1B 209. SLC2A4 265. CDH2 321. FOXO4 377. MIOX 210. SLC5A2 266. CDK7 322. FRMD3 378. MMP14 211. SPP1 267. CDKN1A 323. GAS1 379. MMP16 212. SUMO4 268. CHN2 324. GAS6 380. MMP24 213. TACR1 269. CHPT1 325. GCK 381. MTOR 214. TGFB1 270. CISH 326. GFPT1 382. MYH9 215. TRIB3 271. CLCN5 327. GFPT2 383. NCALD 216. VDR 272. CLEC11A 328. GGT2 384. NCF1 217. VWF 273. CMA1 329. GHR 385. NCF2 218. XRCC1 274. CMC4 330. GHSR 386. NDUFS3 219. ABCC11 275. CNDP2 331. GNB3 387. NEDD4L 220. ACACB 276. CNR1 332. GPC5 388. NFE2 221. ACVRL1 277. CNR2 333. GREM1 389. NFE2L2 222. ADAM10 278. COL8A1 334. HDAC4 390. NFKBIA 223. ADAMTS13 279. COL8A2 335. HFE 391. NGF 224. ADCYAP1 280. CPVL 336. HLA-A 392. NOD2

393. NOS1 449. SIGLEC1 505. ADRA2B 561. UNC13A 394. NOS2 450. SIRT6 506. ASPA 562. VIP 395. NOV 451. SLC12A3 507. ATP2A2 563. XIAP 396. NOX1 452. SLC22A6 508. BDKRB1 564. AAVS1 397. NOX3 453. SLC2A2 509. BDKRB2 565. ADK 398. NPHS1 454. SLC30A8 510. BDNF 566. AHRR 399. NR1H3 455. SLC9A1 511. CACNA1H 567. ANGPT2 400. NSA2 456. SMAD1 512. CD34 568. AOC3 401. ONECUT1 457. SMAD7 513. CNTF 569. API5 402. OSM 458. SOCS1 514. CRH 570. AQP1 403. PC 459. SOCS2 515. ENPP2 571. AQP4 404. PDE5A 460. SOCS3 516. F8 572. CD160 405. PDGFA 461. SOD1 517. FOLH1 573. CD59 406. PDGFB 462. SORBS2 518. GAP43 574. COLEC12 407. PDGFRB 463. SOX9 519. GAPDH 575. CTSH 408. PDK1 464. SPARC 520. GDNF 576. CYBB 409. PDPK1 465. SPON2 521. GFAP 577. CYP2C19 410. PEBP1 466. SRC 522. GIPR 578. CYR61 411. PFKFB2 467. SREBF1 523. HCN2 579. ERAP2 412. PICK1 468. SST 524. HRH1 580. ERBB3 413. PIK3CA 469. STAT1 525. HRH2 581. FAS-AS1 414. PLEKHH2 470. STAT3 526. HSPA5 582. FBXO8 415. POSTN 471. STAT5A 527. IGFBP5 583. FFAR1 416. PRKAA1 472. STH 528. IL4 584. GORAB 417. PRKCB 473. STK11 529. IRAK1 585. GRB2 418. PRKCE 474. SUCNR1 530. KCNJ11 586. HBG2 419. PROC 475. TF 531. MBP 587. HS6ST3 420. PSMD9 476. TGFBR1 532. MME 588. IGF1R 421. PTEN 477. THBD 533. NGFR 589. IL31 422. PTGER1 478. THBS1 534. NRF1 590. IRS1 423. PTGER4 479. THBS2 535. NTF3 591. ITGA2 424. PTGES 480. TIMM44 536. P2RX2 592. ITGB3 425. PTH1R 481. TIMP2 537. P2RX3 593. KDM1A 426. PVT1 482. TKT 538. P2RY1 594. LPO 427. RAF1 483. TLR2 539. P2RY2 595. LTB4R2 428. RCAN1 484. TNF 540. PAK5 596. MAPK7 429. REG1A 485. TNFAIP8 541. PAK6 597. MRPL28 430. RELA 486. TRPC1 542. PECAM1 598. MYO5C 431. RGN 487. TRPV4 543. PMP22 599. NGB 432. RHOD 488. TSC1 544. PPY 600. NME2 433. ROCK1 489. TSC2 545. PRKG1 601. NYS3 434. RPS12 490. TSC22D1 546. PROM1 602. PDHX 435. RPS6 491. UHRF1 547. RHOA 603. PIGF 436. RREB1 492. UMOD 548. RPS6KA6 604. PLXDC1 437. SAA1 493. UNC13B 549. SLC2A3 605. POLR2D 438. SCX 494. UNC5B 550. SLC30A10 606. PSIP1 439. SELE 495. USF2 551. SOD2 607. RBP1 440. SEMA3A 496. UTRN 552. TFAM 608. RHO 441. SERPINB7 497. UTS2R 553. TH 609. ROMO1 442. SERPINE1 498. VDAC1 554. TNFRSF1B 610. SARDH 443. SERPINF1 499. VDAC2 555. TRAF6 611. SLMAP 444. SERPINF2 500. WFS1 556. TRH 612. SMG1 445. SFI1 501. WT1 557. TRPA1 613. SMPD1 446. SGK1 502. XBP1 558. TRPV1 614. SRGN 447. SGK2 503. ZEB2 559. TRPV3 615. SYVN1 448. SGK3 504. ZNF236 560. TSPO 616. TIMP1

617. TUBB3 626. AGXT2 635. TM6SF2 644. PIP 618. UCP1 627. BCO2 636. TPM1 645. RTN1 619. VEGFC 628. CLOCK 637. CHIT1 646. APLN 620. ZNRF1 629. COMT 638. CUBN 647. ESM1 621. CXCR2 630. FADS1 639. GCG 648. L1CAM 622. ACSL1 631. FADS2 640. IGFBP7 649. SERPI3 623. CITED2 632. PNPLA3 641. LRP2 650. TLR9 624. HDAC9 633. PPIA 642. MYD88 625. IRAK4 634. RARRES2 643. NGAL

2.2 Cross Platform Normalization Cross-platform normalization considers all information from tests crosswise over various microarray platforms as a solitary informational index from a similar trial. 30Direct incorporation of informational indexes performed on various microarray stages may acquaint undesirable batch effect due with orderly multiplicative predispositions. The level of trouble present to consolidate different datasets has been named "complexity of data". For instance, coordinating distinctive Affymetrix stages is less problematic to dissect by meta-investigation or cross platform normalization than datasets performed crosswise over altogether different stages. Studies utilizing low intricacy datasets, essentially from the Affymetrix stage, have straightforwardly combined the investigations to develop a quality mark. Cross-platform change and normalization techniques have been produced with an intent to evacuate the artifactual contrasts between information from various microarray stages while saving the basic organic contrasts between conditions. This progression is fundamental, as non-natural contrasts ("clump impacts") in the quality mark disclosure information can cloud genuine organic contrasts found between clinical gatherings. The procedure to perform cross platform normalization has been taken from R package called 31 “virtualArray”. Procedure can be split up into several steps. The first two steps are pre-processing of datasets. Steps 3 and 4 acts on one batch/chip type at a time, whereas the last three steps are applied to all batches/chip types simultaneously, resulting ultimately in the creation of a new “ExpressionSet” object. A scheme of all steps is shown in Figure 1.1.

Figure 1.1

Scheme of the steps performed for cross platform normalization.

2.2.1 Loading and storage of raw data

Firstly, raw data from the studies were fetched from the NCBI GEO database. The raw data of each dataset are imported into R and stored in a regular ExpressionSet by means of the 32 GEOquery package:

 library(GEOquery)  GSE38642<-getGEO("GSE38642")  GSE26887<-getGEO("GSE26887")  GSE8157<-getGEO("GSE8157")  GSE13760<-getGEO("GSE13760")  GSE9006<-getGEO("GSE9006")  GSE12643<-getGEO("GSE12643")  GSE6798<-getGEO("GSE6798")  GSE39825<-getGEO("GSE39825")  GSE54350<-getGEO("GSE54350")  GSE55650<-getGEO("GSE55650")  GSE16415<-getGEO("GSE16415")  GSE23343<-getGEO("GSE23343")  GSE25724<-getGEO("GSE25724")

 gse38642<-GSE38642[[1]]  gse26887<-GSE26887[[1]]  gse8157<-GSE8157[[1]]  gse13760<-GSE13760[[1]]  gse9006<-GSE9006[[1]]  gse12643<-GSE12643[[1]]  gse6798<-GSE6798[[1]]  gse39825<-GSE39825[[1]]  gse54350<-GSE54350[[1]]  gse55650<-GSE55650[[1]]  gse16415<-GSE16415[[1]]  gse23343<-GSE23343[[1]]  gse25724<-GSE25724[[1]]

2.2.2 Transformations of raw data Even samples from the same platform may yield raw data in different formats dependent on the hardware employed or the mode of measurement. Thus, each dataset needs to be transformed to one common scale (e.g. log2, log10 or linear) and one common precision (12, 14, 16 or 20 bit) by using standard R functions on the "exprs" slot of the ExpressionSets. In the case of personally collected data the precision of the raw data may be known. It is also possible, that this information was deposited along with the data in an NCBI GEO database entry. If only information on the scanner used is available, the precision can possibly be obtained from the manufacturer’s website.

Datasets has been transformed as followed-

 exprs(gse38642) <- exprs(gse38642)  exprs(gse25724) <- exprs(gse25724)  exprs(gse13760) <- log2(exprs(gse13760))

 exprs(gse26887) <- exprs(gse26887)  exprs(gse8157) <- log2(exprs(gse8157))  exprs(gse12643) <- exprs(gse12643)  exprs(gse6798) <- log2(exprs(gse6798))  exprs(gse55650) <- exprs(gse55650)  exprs(gse9006) <- log2(exprs(gse9006))  exprs(gse39825) <- log2(exprs(gse39825))  exprs(gse54350) <- log2(exprs(gse54350))  exprs(gse16415) <- log2(exprs(gse16415))  exprs(gse23342) <- exprs(gse23343)

2.2.3 Annotation of raw data

Raw data are comprised of expression levels annotated with manufacturer specific IDs that cannot be matched across platforms directly. In order to allow a later matching of corresponding pairs, step 3 annotates common identifiers to each single dataset. The common identifier used is gene symbols (named "SYMBOL" in the annotation packages). However, any identifier present in the annotation packages, including identifiers for genes, transcripts or proteins can be used.

Annotation files for the datasets used are given in Table 2.2 –

Table 2.2: Annotation files for the datasets collected GSE ID Annotation file GSE38642 hugene10sttranscriptcluster GSE25724 hgu133a GSE13760 hgu133a2 GSE26887 hugene10sttranscriptcluster GSE8157 hgu133plus2 GSE312643 hgu95av2 GSE6798 hgu133plus2 GSE55650 hgu133plus2 GSE9006 hgu133a GSE39825 hgu95av2 GSE54350 illuminaHumanv4 GSE23343 hgu133plus2 GSE16415 -

For GSE16415 annonation table has been customized. The datasets can be annotated using following

 library("annotationfile.db")  names=select(annotationfile.db, row.names(exprs(GSEID)),c("SYMBOL"))  b<-sapply(1:length(rownames(exprs(GSEID))),function(i){ print(i) query<-rownames(exprs(GSEID))[i] result<-which(names[,1]==query)[1] return(names[result,2]) })  rownames(exprs(GSEID))<-b

2.2.4 Collapsing of redundant probe sets In many chips, several probes or probe sets target the same gene, transcript or protein, resulting in > 1 entry for otherwise unique identifiers. Thus, before the annotated common identifiers can be matched, redundant rows need to be collapsed to a single value. exprs(GSEID)<- aggregate(list(GSEID),by = list(rowname(exprs(GSEID))), median)

2.2.5 Removal of batch effects and merging datasets

For batch effect removal and merging of datasets “inSilicoMerging” package has been used. InSilicoMerging R/Bioconductor package allows consistent retrieval, integration and analysis of publicly available microarray gene expression data sets. Inside the inSilicoMerging package a set of five visual and six quantitative validation measures are available as well. The different merging methods implemented in the inSilicoMerging package can be applied on the pre-processed ExpressionSets by calling a single function merge. For example, simple combination without batch effect removal can be done as follows:

> merge(esets, method="NONE");

With esets a list of ExpressionSet objects. The method parameter can be one of the options described above: BMC, COMBAT, DWD, GENENORM, NONE or XPN. For this analysis COMBAT has been used for batch effect removal.

Here 6 different ExpressionSet objects has been created containing tissue wise ExpressionSet objects.

 library(inSilicoMerging);  eset=list(gse38642, gse25724)  mergecombat_pancreas=merge(esets = eset, method = "COMBAT")  eset=list(gse13760, gse26887)  mergecombat_heart=merge(esets = eset, method = "COMBAT")  eset=list(gse8157, gse12643, gse6798, gse55650)  mergecombat_muscle=merge(esets = eset, method = "COMBAT")  eset=list( gse9006, gse39825)  mergecombat_blood=merge(esets = eset, method = "COMBAT")  eset=list( gse54350, gse16415)  mergecombat_adipose=merge(esets = eset, method = "COMBAT")

2.2.6 COMBAT for batch effect removal

Non-biological experimental variation or batch effects are commonly observed across multiple batches of microarray experiments, often rendering the task of combining data from these batches difficult.33 The ability to combine microarray data sets is advantageous to researchers to increase statistical power to detect biological phenomena from studies where logistical considerations restrict sample size or in studies that require the sequential hybridization of arrays. In general, it is inappropriate to combine data sets without adjusting for batch effects. Methods have been proposed to filter batch effects from data, but these are often complicated and require large batch sizes (>25) to implement. Because the majority of microarray studies are conducted using much smaller sample sizes, existing methods are not sufficient. COMBAT uses

24 parametric and nonparametric empirical Bayes frameworks for adjusting data for batch effects that is robust to outliers in small sample sizes and performs comparable to existing methods for large samples. Empirical Bayes (EB) (also known as Extended Johnson-Li-Rabinovich or COMBAT) is a method using estimations for the LS parameters (mean and variance) for each gene. The parameters are estimated by pooling information from multiple genes with similar expression characteristics in each batch. There exist both a parametric and nonparametric approach; we give a concise explanation, and details can be found in the original publication. It is assumed that meaured gene expression values of gene i in sample j in each batch can be expressed as a specialization of Equation (1) as:

where αi is the gene expression not related to any known covariates, C is a design matrix for sample conditions (known covariates), i is the vector of regression coefficients corresponding to C, and are the additive and multiplicative batch effects for gene i, respectively, and are noise terms. are assumed to follow a normal distribution with mean zero and variance . The first step in EB is to standardize the data using estimates , , and for the corresponding variables. The standardized gene expression zij is assumed to be normally distributed according to and is given by

The batch effect adjusted data are given by

where and are estimates of batch effect parameters in Equation estimated using parametric or non-parametric empirical priors. In case of parametric priors, it is assumed that and , where , and are estimated empirically. Equivalent properties hold for the terms of .

2.3 Filtering dataset for Type 2 Diabetes and getting the normal range

In order to find out the range of expression of genes that implicate complications in type 2 diabetes for normal people, the normalized dataset is needed to be filtered out for required genes. Further, to find the range of expression for each gene, two types of ranges are calculated (a) Actual range is calculated by calculating minimum and maximum expression value for each gene for each tissue. (b) 99% confidence interval for each gene is also calculated for each tissue.

2.3.1 Confidence interval

In statistics, 34 a confidence interval (CI) is a type of interval estimate (of a population parameter) that is computed from the observed data. The confidence level is the frequency (i.e., the proportion) of confidence intervals that contain the true value of their corresponding parameter. In other words, if confidence intervals are constructed using a given confidence level in an infinite number of independent experiments, the proportion of those intervals that contain the true value of the parameter will match the confidence level. Confidence intervals consist of a range of values (interval) that act as good estimates of the unknown population parameter. The desired level of confidence is set by the researcher (not determined by data). Most commonly, the 35 95% confidence level is used. However, other confidence intervals can be used, for example, 90%, 95%, and 99%. Factors affecting the width of the confidence interval include the size of the sample, the confidence level, and the variability in the sample. A larger sample size normally will lead to a better estimate of the population parameter. When the population standard deviation is known, the formula for a confidence interval (CI) for a population mean is

deviation, n is the sample size, and z* represents the appropriate z*-value from the standard normal distribution for your desired confidence level. z*–values for Various Confidence Levels are given in Table 2.3.

Table 2.3

Confidence Level z*-value 80% 1.28 90% 1.645 (by convention) 95% 1.96 98% 2.33 99% 2.58

Chapter - 3

T2DiGER- Type 2 Diabetes Gene Expression Report

Gene expression analysis is the method of analysing the activity (the expression) of thousands of genes, in isolation or all at once, to create a global picture of biological functions. Gene expression analysis has recently been at the forefront of advance in personalized medicine, notably in the field of cancer and transplantation. Type 2 diabetes is omnipresent disease.

T2DiGER is a web based tool which uses gene expression analysis to generate a gene expression report. Similar, to the report that path labs give after blood tests or etc., T2DiGER generates a report based on gene expression values of a person.

T2DiGER takes gene expression values of a person as input and generates a report which tells which of the genes that implicate complications in type 2 diabetes are present in the person. Also, it compares the gene expression values of the person with the normal range of the gene causing complications in T2D. If the gene expression value of the person does not lie in normal range then T2DiGER also shows the type 2 diabetes complications that are related to the gene . Working in tandem, researchers and doctors can use this tool to find possible outcomes in Diabetes which will be a boon for patients.

The procedure used to implement T2DiGER has been described below.

3.1 T2DiGER User Interface

The display of T2DiGER has been made user friendly and informative. T2DiGER user interface has been developed using HTML, PHP and jQuery. Also, it calls R script to do processing on the data input by user

3.2 T2DiGER User Input

There are two types of inputs provided in T2DiGER, for the two functions performed by T2DiGER. The first and main function of T2DiGER is to take gene expression data and the type of tissue of a person as input and do the analysis. For this input has to be provided in csv format, in which first column has the list of genes and second column has the expression values. The user input looks like figure 3.1

Figure 3.1: User input for function 1 27

The second function performed by T2DiGER is providing gene names for probe ids from 9 different microarray platforms. For this user has to provide platform name and list of probe ids in csv format. The above input looks like Figure 3.2

Figure 3.2: User input for function 1

3.3 T2DiGER Background Operation

As mentioned earlier T2DiGER performs two functions. First is to take gene expression values of a person as input, analyse the data and generate type 2 diabetes gene expression report. Second one is to match probe ids to the respective gene names. . This function has been provided to help user in creating the user input for generating gene expression report. The two of the procedures are explained in detail below.

3.3.1 Generating Gene Expression Report

Steps for generating gene expression report are as follows – 1) Firstly the gene expression data of user is taken as input and stored in the respective directory. Desired format of the input is already explained. Also, the type of the tissue is selected from the list and the further operation is performed on the data according to that only. The tissues considered for analysis are pancreas, blood, muscle, heart, adipose and liver. 2) Then the R script which performs the analysis is called by the user interface. 3) The R script reads the gene expression data, the tissue table (which consists of normal range and complications related to the genes in that particular tissue) and median values for the gene expression values. 4) Since, in the gene expression data one gene can have multiple expression values, so the redundant data is replaced with the median of all the expression values for that particular gene Also the data is filtered for genes that implicated complication in type two diabetes. 5) Then, in order to bring the user input gene expression data to the scale of already normalized gene expression values, the user input data is normalized against the median of already normalized gene expression values of the control samples. For this purpose quantile normalization (explained in 4.3.2) is used. 6) After normalization, the user gene expression data is compared to the range of expression values in normal sample and the output table is created. 7) Lastly, the output table is stored in the desired directory in the csv format , which will be further read and displayed by user interface. The detailed R script is provided in Appendix.

3.3.2 Quantile Normalization

In statistics, quantile normalization is a technique for making two distributions identical in statistical properties. To quantile-normalize a test distribution to a reference distribution of the same length, sort the test distribution and sort the reference distribution. The highest entry in the test distribution then takes the value of the highest entry in the reference distribution, the next highest entry in the reference distribution, and so on, until the test distribution is a perturbation of the reference distribution.

To quantile normalize two or more distributions to each other, without a reference distribution, sort as before, then set to the average (usually, arithmetic mean) of the distributions. So the highest value in all cases becomes the mean of the highest values, the second highest value becomes the mean of the second highest values, and so on.

Generally a reference distribution will be one of the standard statistical distributions such as the Gaussian distribution or the Poisson distribution. The reference distribution can be generated randomly or from taking regular samples from the cumulative distribution function of the distribution. However, any reference distribution can be used.

3.3.3 Matching Probe Ids to Gene Names

The steps to match Probe Ids to Gene Names has been explained in detail below

1) Firstly, the user input file in desired format is taken through user interface in the format already explained. Also, the platform details are taken from user. This function has been provided for 9 microarray platforms which are hgu133a, hgu133a2, hgu95av2, hgug4112a, hugene10sttranscriptcluster, illuminaHumanv3, illuminaHumanv4, u133x3p, hgu133aplus2. 2) After taking the input, R script is called to get the gene names for the given probe ids and the output table is created. 3) The output table is then stored in the desired directory which can be later downloaded by user.

3.4 T2DiGER output

For the two functions performed by T2DiGER, it provides two outputs. For the first function T2DiGER provides a gene expression report and for the second function it provides a file that contains gene names matched to the probe ids. The gene expression report has 13 columns. The 1st column consists of the gene names. The 2nd column has the remarks which tell if the user gene expression value is in normal range or not. The 3rd column has the normalized gene expression values of the user. The 4th and 5th column contains minimum and maximum gene expression value for control samples. The 6th and 7th column as the 99% confidence range for gene expression values in control sample. This is provided for the further comparison of used gene expression value to the normal range. If the gene expression value of the user not in normal range then the 8th to 12th columns has details related to related to type 2 diabetes complications related to the gene and the 13th column has link to T2DiACoD to provide further insight about the gene otherwise 8th to 13th column is empty. This report is displayed on screen in tabular format and can also be downloaded in csv format.

After matching probe ids to gene names, an output table is created has 2 columns. 1st column has the probe ids and the 2nd column contains the matched gene names. This file is in csv format and can only be downloaded.

Chapter - 4

Results

4.1 Evaluation of normalized datasets for tissue wise normal samples

Tissue wise collected samples have already been discussed in section 2.1. In here we will demonstrate the effect of various normalization on the tissue wise datasets. Figure 3.1 to Fig 3.6 displays the box-plot of tissue wise raw and LS parameter transformed datasets. L/S parameter adjustment is done before implementing COMBAT for cross platform normalization. Red and blue colour is used to represent samples from different experiments.

(a) Raw samples from pancreas

(b) LS transformed samples from pancreas Figure 4.1: Boxplot to show comparison of raw and L/S transformed samples from pancreas (a) raw samples (b) L/S transformed

(a) Raw samples from heart

(b) LS transformed samples from heart

Figure 4.2: Boxplot to show comparison of raw and L/S transformed samples from heart (a) raw samples (b) L/S transformed

(a) Raw samples from blood

(b) LS transformed samples from blood

Figure 4.3: Boxplot to show comparison of raw and L/S transformed samples from blood (a) raw samples (b) L/S transformed

(a) Raw samples from muscle

(b) LS transformed samples from muscle

Figure 4.4: Boxplot to show comparison of raw and L/S transformed samples from muscle (a) raw samples (b) L/S transformed

(a) Raw samples from adipose

(b) LS transformed samples from adipose

Figure 4.5: Boxplot to show comparison of raw and L/S transformed samples from adipose (a) raw samples (b) L/S transformed

(a) Raw samples from liver

(b) LS transformed samples from liver

Figure 4.6: Boxplot to show comparison of raw and L/S transformed samples from liver (a) raw samples (b) L/S transformed

After normalization, in order to integrate the data from different microarray platforms, batch effect removal is required. Here COMBAT has been used for batch effect removal which has been already explained in section 2.2.5. Figure 3.7 to figure 3.12 displays the tissue wise control samples after batch effect correction. For this, alphabetically first 25 genes expressed in each tissue is used.

adipose control samples after batch effect correction

AGXT2 AGTR1 AGT AGER ADRA2B ADM ADK ADIPOR1

ADIPOQ GSM412611 ADH1B GSM412610 ADCYAP1 GSM412609 ADAMTS13 GSM412608 ADAM17 GSM412607 genes ADAM10 GSM1313617 ACVRL1 GSM1313615 ACVR1C GSM1313614 ACSL1 GSM1313613 ACE2 GSM1313612 ACE GSM1313608 ACAT1 ACACB ABO ABCG1 ABCC11 ABCA1

0 2 4 6 8 10 expression values

Figure 4.7: Bar graph showing gene expression values of control samples from liver tissue after batch effect removal.

blood control samples after batch effect correction

ALB GSM979908 AKT1 GSM979907 AKR1B10 GSM979906 AKR1B1 GSM979905 AHSG GSM979904 AHSA1 GSM979903 AGTR1 GSM228666 AGT GSM228665

AGER GSM228664

ADM GSM228663 GSM228581 ADK GSM228580 ADIPOQ GSM228579

genes ADH1B GSM228578 ADCYAP1 GSM228577 ADAM17 GSM228576 ADAM10 GSM228575 ACVRL1 GSM228574

ACSL1 GSM228573

ACE GSM228572 GSM228571 ACAT1 GSM228570 ACACB GSM228569 ABO GSM228568 ABCG1 GSM228567 ABCA1 GSM228566 0 2 4 6 8 10 12 14 GSM228565 expression values

Figure 3.4: Bar graph showing gene expression values of control samples from blood tissue after batch effect removal.

heart control samples after batch effect correction

AHSG

AHSA1 AGTR1 AGT

AGER GSM662162 ADRA2B GSM662161 ADM GSM662160 ADK GSM662159 ADIPOR1 GSM662158 ADIPOQ GSM346589 GSM346588 ADH1B GSM346587 ADCYAP1 GSM346585

genes ADAMTS13 GSM346584 ADAM17 GSM346581 ADAM10 GSM346578 ACVRL1 GSM346576 ACSL1 GSM346575 ACE2 GSM346573 ACE GSM346570 GSM346568 ACAT1 GSM346566 ACACB GSM346561 ABO ABCG1 ABCA1

0 2 4 6 8 10 12 expression values

Figure 4.9: Bar graph showing gene expression values of control samples from heart tissue after batch effect removal.

liver control samples after batch effect correction

AGT

AGER

ADRA2B

ADM

ADK

ADIPOR1

ADIPOQ

ADH1B

ADCYAP1

ADCY5 GSM572806 ADAMTS13 GSM572805 ADAM17 GSM572804

genes ADAM10 GSM572803 ACVRL1 GSM572802 ACVR1C GSM572801 ACSL1 GSM572800

ACE2

ACE

ACAT1

ACACB

ABO

ABCG1

ABCC11

ABCA1

0 0.5 1 1.5 2 2.5 expression values

Figure 4.10: Bar graph showing gene expression values of control samples from liver tissue after batch effect removal.

muscle control samples after batch effect correction

ALB GSM1341157 AKT1 GSM1341156 AKR1B10 GSM1341155 AKR1B1 GSM1341154 AHSG GSM1341153 AHSA1 GSM1341146 AGTR1 GSM1341145 AGT GSM1341144

AGER GSM1341143

ADM GSM1341142 GSM1341141 ADK GSM156184 ADIPOQ GSM156181

genes ADH1B GSM156180 ADCYAP1 GSM156179 ADAM17 GSM156178 ADAM10 GSM156177 ACVRL1 GSM156176

ACSL1 GSM156171 GSM156170 ACE GSM155729 ACAT1 GSM155644 ACACB GSM155643 ABO GSM155631 ABCG1 GSM317341 ABCA1 GSM317340

0 2 4 6 8 10 12 GSM317339 expression values

Figure 4.11: Bar graph showing gene expression values of control samples from muscle tissue after batch effect removal.

pancreas control samples after batch efftect correction

AKR1B1 GSM631761 AHSG GSM631760 AHSA1 GSM631759 AGTR1 GSM631758 AGT GSM631757 ADRA2B GSM631756 ADM GSM631755 ADK GSM946762

ADIPOR1 GSM946759

ADIPOQ GSM946758 GSM946757 ADH1B GSM946756 ADCYAP1 GSM946755

genes ADAMTS13 GSM946754 ADAM17 GSM946753 ADAM10 GSM946752 ACVRL1 GSM946751 ACSL1 GSM946750

ACE2 GSM946749 GSM946748 ACE GSM946744 ACAT1 GSM946743 ACACB GSM946742 ABO GSM946741 ABCG1 GSM946738 ABCA1 GSM946737

0 2 4 6 8 10 12 GSM946736 expression values

Figure 4.12: Bar graph showing gene expression values of control samples from pancreatic tissue after batch effect removal.

4.2 Tissue tables

After, the data is cross platform normalized the tissue wise table is created which contains the normal range, 99% confidence interval range (explained in section 2.3.1 ) and complications related to the genes. The tissue table is used in generation of gene expression report. The sample of tissue table is given below. The detailed tissue table is given in Appendix.

Table 4.1: sample tissue table

Genes Actual Actual 99% CI 99% CI complication1 complication complication complication complication5 Min Max Min Max 2 3 4 1 ABCA1 4.045497 6.125943 4.405093 5.360109 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 2 ABCC11 1.078017 2.605749 1.477773 2.132796 NA NA NA Nephropathy NA

3 ABCG1 2.957539 5.093512 3.216097 4.315623 Cardiovascular NA Atherosclerosi NA NA diseases s 4 ABO 0.944456 2.604139 1.734173 2.493131 Cardiovascular NA NA NA NA diseases 5 ACACB 3.603468 7.734768 4.382535 6.124712 NA NA NA Nephropathy NA

6 ACAT1 4.1079 6.103411 4.979755 5.956635 NA NA Atherosclerosi NA NA s 7 ACE 2.908547 3.466215 3.043873 3.333745 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 8 ACE2 1.189019 2.83352 1.469647 2.287943 Cardiovascular NA NA Nephropathy NA diseases 9 ACSL1 6.074148 8.054148 6.528475 7.454662 NA NA Atherosclerosi NA NA s 10 ACVR1 2.310198 4.899523 2.895785 4.126829 Cardiovascular NA NA NA NA C diseases

Chapter-5

Summary and Conclusion

Every day, millions of people are taking medications that will not help them. The top ten highest-grossing drugs in the United States help between 1 in 25 and 1 in 4 of the people who take them. There are even drugs that are harmful to certain ethnic groups because of the bias towards participants in classical clinical trials.

Recognition that physicians need to take individual variability into account is driving huge interest in 'precision' medicine. Gene expression has recently been at the forefront of advance in personalized medicine, notably in the field of cancer and transplantation. In this project gene expression analysis has been used to find the range of expression of genes that implicate complications in case of a healthy individual. This analysis has been done tissue wise. T2DiGER is the web based tool which will help researchers and doctors to compare gene expression of patients to normal person and help the patients in taking necessary measures.

Appendix

R Scripts Cross platform normalization sand getting the range

#including library to fetch data from GEO library(GEOquery)

##------#fetching desired from GEO GSE38642<-getGEO("GSE38642") GSE26887<-getGEO("GSE26887") GSE8157<-getGEO("GSE8157") GSE13760<-getGEO("GSE13760") GSE26168<-getGEO("GSE26168") GSE9006<-getGEO("GSE9006") GSE20966<-getGEO("GSE20966") GSE12643<-getGEO("GSE12643") GSE6798<-getGEO("GSE6798") GSE21815<-getGEO('GSE21815') GSE35279<-getGEO("GSE35279") GSE39825<-getGEO("GSE39825") GSE54350<-getGEO("GSE54350") GSE55650<-getGEO("GSE55650") GSE29226<-getGEO("GSE29226") GSE16415<-getGEO("GSE16415") GSE23343<-getGEO("GSE23343") GSE25724<-getGEO("GSE25724") GSE29221<-getGEO("GSE29221")

#fetching ExpressionSert objects from the fetched data GSE38642<-GSE38642[[1]] GSE26887<-GSE26887[[1]] GSE8157<-GSE8157[[1]] GSE13760<-GSE13760[[1]] GSE9006<-GSE9006[[1]] GSE12643<-GSE12643[[1]] GSE6798<-GSE6798[[1]] GSE39825<-GSE39825[[1]] GSE54350<-GSE54350[[1]] GSE55650<-GSE55650[[1]] GSE16415<-GSE16415[[1]] GSE23343<-GSE23343[[1]] GSE25724<-GSE25724[[1]] gse38642<-GSE38642[[1]] gse26887<-GSE26887[[1]] gse8157<-GSE8157[[1]] gse13760<-GSE13760[[1]] gse26168<-GSE26168[[2]] gse9006<-GSE9006[[1]] gse20966<-GSE20966[[1]] gse12643<-GSE12643[[1]] gse6798<-GSE6798[[1]] gse21815<-GSE21815[[1]] gse35279<-GSE35279[[1]] gse39825<-GSE39825[[1]] gse54350<-GSE54350[[1]] gse55650<-GSE55650[[1]] gse29226<-GSE29226[[1]] gse16415<-GSE16415[[1]] gse23343<-GSE23343[[1]] gse25724<-GSE25724[[1]] gse29221<-GSE29221[[1]]

##------#associating the annotation file with the expressionsets annotation(gse38642)="hugene10sttranscriptcluster" annotation(gse26887)="hugene10sttranscriptcluster" annotation(gse8157)="hgu133plus2" annotation(gse13760)="hgu133a2" annotation(gse26168)="illuminaHumanv3" annotation(gse9006)="hgu133a"

45 annotation(gse20966)="u133x3p" annotation(gse12643)="hgu95av2" annotation(gse6798)="hgu133plus2" annotation(gse21815)="hgug4112a" annotation(gse35279)="hgug4112a" annotation(gse39825)="hgu95av2" annotation(gse54350)="illuminaHumanv4" annotation(gse55650)="hgu133plus2" annotation(gse29226)="illuminaHumanv3" annotation(gse23343)="hgu133plus2" annotation(gse25724)="hgu133a" annotation(gse29221)="illuminaHumanv3"

##------# replacing probe ids with the gene names using desired annotation package from 1 to 19 #1 library("hugene10sttranscriptcluster.db") names=select(hugene10sttranscriptcluster.db, row.names(exprs(gse38642)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse38642))),function(i){ print(i) query<-rownames(exprs(gse38642))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse38642))<-b

#2 library("hugene10sttranscriptcluster.db") names=select(hugene10sttranscriptcluster.db, row.names(exprs(gse26887)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse26887))),function(i){ print(i) query<-rownames(exprs(gse26887))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse26887))<-b

#3 library("hgu133plus2.db") names=select(hgu133plus2.db, row.names(exprs(gse8157)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse8157))),function(i){ print(i) query<-rownames(exprs(gse8157))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse8157))<-b

#4 library("hgu133a2.db") names=select(hgu133a2.db, row.names(exprs(gse13760)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse13760))),function(i){ print(i) query<-rownames(exprs(gse13760))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse13760))<-b

#5 annotation(gse26168)="illuminaHumanv3" library("illuminaHumanv3.db") names=select(illuminaHumanv3.db, row.names(exprs(gse26168)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse26168))),function(i){ print(i) query<-rownames(exprs(gse26168))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse26168))<-b

#6 library("hgu133a.db") names=select(hgu133a.db, row.names(exprs(gse9006)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse9006))),function(i){ print(i) query<-rownames(exprs(gse9006))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse9006))<-b

#7 library("u133x3p.db") names=select(u133x3p.db, row.names(exprs(gse20966)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse20966))),function(i){ print(i) query<-rownames(exprs(gse20966))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse20966))<-b

#8 library("hgu95av2.db") names=select(hgu95av2.db, row.names(exprs(gse12643)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse12643))),function(i){ print(i) query<-rownames(exprs(gse12643))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse12643))<-b

#9 library("hgu133plus2.db") names=select(hgu133plus2.db, row.names(exprs(gse6798)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse6798))),function(i){ print(i) query<-rownames(exprs(gse6798))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse6798))<-b

#10 annotation(gse21815)="hgug4112a" library("hgug4112a.db") names=select(hgug4112a.db, row.names(exprs(gse21815)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse21815))),function(i){ print(i) query<-rownames(exprs(gse21815))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse21815))<-b

#11 library("hgug4112a.db") names=select(hgug4112a.db, row.names(exprs(gse35279)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse35279))),function(i){ print(i) query<-rownames(exprs(gse35279))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse35279))<-b

#12 library("hgu95av2.db")

47 names=select(hgu95av2.db, row.names(exprs(gse39825)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse39825))),function(i){ print(i) query<-rownames(exprs(gse39825))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse39825))<-b

#13 library("illuminaHumanv4.db") names=select(illuminaHumanv4.db, row.names(exprs(gse54350)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse54350))),function(i){ print(i) query<-rownames(exprs(gse54350))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse54350))<-b

#14 library("hgu133plus2.db") names=select(hgu133plus2.db, row.names(exprs(gse55650)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse55650))),function(i){ print(i) query<-rownames(exprs(gse55650))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse55650))<-b

#15 annotation(gse29226)="illuminaHumanv3" library("illuminaHumanv3.db") names=select(illuminaHumanv3.db, row.names(exprs(gse29226)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse29226))),function(i){ print(i) query<-rownames(exprs(gse29226))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse29226))<-b

#16 b<-sapply(1:length(rownames(exprs(gse16415))),function(i){ print(i) query<-rownames(exprs(gse16415))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse16415))<-b

#17 library("hgu133plus2.db") names=select(hgu133plus2.db, row.names(exprs(gse23343)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse23343))),function(i){ print(i) query<-rownames(exprs(gse23343))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse23343))<-b

#18 library("hgu133a.db") names=select(hgu133a.db, row.names(exprs(gse25724)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse25724))),function(i){ print(i) query<-rownames(exprs(gse25724))[i]

result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse25724))<-b

#19 library("illuminaHumanv3.db") names=select(illuminaHumanv3.db, row.names(exprs(gse29221)), c("SYMBOL")) b<-sapply(1:length(rownames(exprs(gse29221))),function(i){ print(i) query<-rownames(exprs(gse29221))[i] result<-which(names[,1]==query)[1] return(names[result,2]) }) rownames(exprs(gse29221))<-b

##------#cross platform normalization of pancreatic samples #Visualizing raw data boxplot(exprs(GSE38642[,1:3]),at=1:3,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=F,las=3, col="red") boxplot(exprs(GSE25724[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=T,las=3, col="blue") title(ylab="expression value",main="Comparison of raw expression values from 2 datasets from pancreas")

#Visualizing L/S transformed data boxplot(exprs(GSE38642[,1:3]),at=1:3,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=F,las=3, col="red") boxplot(exprs(GSE25724[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=T,las=3, col="blue") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 2 datasets from pancreas")

#L/S transformation of data exprs(gse38642) <- exprs(gse38642) exprs(gse25724) <- exprs(gse25724) eset=list(gse38642, gse25724)

#merging the pancreatic samples after batch effect removal using COMBAT mergecombat_pancreas=merge(esets = eset, method = "COMBAT")

#cross platform normalization of heart samples #Visualizing raw data boxplot(exprs(gse13760[,1:3]),at=1:3,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=F,las=3, col="red") boxplot(exprs(gse26887[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=T,las=3, col="blue") title(ylab="expression value",main="Comparison of raw expression values from 2 datasets from heart")

#Visualizing L/S transformed data boxplot(log2(exprs(gse13760[,1:3])),at=1:3,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=F,las=3, col="red") boxplot(exprs(gse26887[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=T,las=3, col="blue") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 2 datasets from heart")

#L/S transformation of data exprs(gse13760) <- log2(exprs(gse13760)) exprs(gse26887) <- exprs(gse26887) eset=list(gse13760, gse26887)

#merging the heart samples after batch effect removal using COMBAT mergecombat_heart=merge(esets = eset, method = "COMBAT")

#cross platform normalization of musclet samples #Visualizing raw data boxplot(exprs(GSE8157[,1:3]),at=1:3,xlim=c(0.5,12.5),ylim=c(1,50000),log="y",add=F,las=3, col="red") boxplot(exprs(GSE12643[,1:3]),at=4:6,xlim=c(0.5,12.5),ylim=c(1,50000),log="y",add=T,las=3, col="blue") boxplot(exprs(GSE6798[,1:3]),at=7:9,xlim=c(0.5,12.5),ylim=c(1,50000),log="y",add=T,las=3, col="red") boxplot(exprs(GSE55650[,1:3]),at=10:12,xlim=c(0.5,12.5),ylim=c(1,50000),log="y",add=T,las=3, col="blue") title(ylab="expression value",main="Comparison of raw expression values from 4 datasets from muscle")

#Visualizing L/S transformed data boxplot(log2(exprs(GSE8157[,1:3])),at=1:3,xlim=c(0.5,12.5),ylim=c(1,20),log="y",add=F,las=3, col="red") boxplot(exprs(GSE12643[,1:3]),at=4:6,xlim=c(0.5,12.5),ylim=c(1,20),log="y",add=T,las=3, col="blue") boxplot(log2(exprs(GSE6798[,1:3])),at=7:9,xlim=c(0.5,12.5),ylim=c(1,20),log="y",add=T,las=3, col="red") boxplot(exprs(GSE55650[,1:3]),at=10:12,xlim=c(0.5,12.5),ylim=c(1,20),log="y",add=T,las=3, col="blue") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 4 datasets from muscle")

#L/S transformation of data exprs(gse8157) <- log2(exprs(gse8157)) exprs(gse12643) <- exprs(gse12643) exprs(gse6798) <- log2(exprs(gse6798)) exprs(gse55650) <- exprs(gse55650) eset=list(gse8157, gse12643, gse6798, gse55650)

#merging the muscle samples after batch effect removal using COMBAT mergecombat_muscle=merge(esets = eset, method = "COMBAT")

##cross platform normalization of blood samples #Visualizing raw data boxplot(exprs(GSE9006[,1:3]),at=1:3,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=F,las=3, col="blue") boxplot(exprs(GSE39825[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=T,las=3, col="red") title(ylab="expression value",main="Comparison of raw expression values from 2 datasets from blood")

#Visualizing L/S transformed data boxplot(log2(exprs(GSE9006[,1:3]))/20*16,at=1:3,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=F,las=3, col="blue") boxplot(log2(exprs(GSE39825[,1:3]))/20*16,at=4:6,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=T,las=3, col="red") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 2 datasets from blood")

#L/S transformation of data exprs(gse9006) <- log2(exprs(gse9006)) exprs(gse39825) <- log2(exprs(gse39825))

#merging the blood samples after batch effect removal using COMBAT eset=list( gse9006, gse39825) mergecombat_blood=merge(esets = eset, method = "COMBAT")

##cross platform normalization of adipose samples #Visualizing raw data boxplot(exprs(GSE54350[,1:3]),at=1:3,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=F,las=3, col="blue") boxplot(exprs(GSE16415[,1:3]),at=4:6,xlim=c(0.5,6.5),ylim=c(1,50000),log="y",add=T,las=3, col="red") title(ylab="expression value",main="Comparison of raw expression values from 2 datasets from adipose tissue")

#Visualizing L/S transformed data boxplot(log2(exprs(GSE54350[,1:3])),at=1:3,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=F,las=3, col="blue") boxplot(log2(exprs(GSE16415[,1:3])),at=4:6,xlim=c(0.5,6.5),ylim=c(1,20),log="y",add=T,las=3, col="red") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 2 datasets from adipose tissue")

#L/S transformation of data exprs(gse54350) <- log2(exprs(gse54350)) exprs(gse16415) <- log2(exprs(gse16415)) eset=list( gse54350, gse16415) #merging the adipose samples after batch effect removal using COMBAT mergecombat_adipose=merge(esets = eset, method = "COMBAT")

##cross platform normalization of liver samples #Visualizing raw data boxplot(exprs(gse23343[,1:3]),at=1:3,xlim=c(0.5,3.5),ylim=c(1,50000),log="y",add=F,las=3, col="red") title(ylab="expression value",main="Comparison of raw expression values from 1 datasets from liver")

#Visualizing L/S transformed data boxplot(log2(exprs(gse23343[,1:3])),at=1:3,xlim=c(0.5,3.5),ylim=c(1,20),log="y",add=F,las=3, col="red") abline(h=16) title(ylab="expression value",main="Comparison of L/S transformed expression values from 1 datasets from liver")

##------#extraction merged table of expression values from expressionset objects adipose=exprs(mergecombat_adipose) blood=exprs(mergecombat_blood) heart=exprs(mergecombat_heart) muscle=exprs(mergecombat_muscle) pancreas=exprs(mergecombat_pancreas) liver=exprs(gse23343)

#deleting samples other than controls pancreas=pancreas[,-c(11,12, 40,41, 46:48,61,62,71:76)] heart=heart[,-c(1,3,4,8,13,15,18,27:45)] muscle=muscle[,-c(1:20, 34:43,44:53,77:92,99:104,110:115)]

50 blood=blood[,-c(21:101,106:117, 124:127)] adipose=adipose[,-c(1,3:5,10,12,18:22)] liver=liver[,-c(8:17)]

#fetching table containing list of genes implicating complications in type 2 diabetes t2d_genes=read.csv("F:/thesisdata/t2dgenes.csv")

#filtering tissue wise tables containg gene expression data of control samples for genes implicating complications in type 2 diabetes index=row.names(pancreas) %in% t2d_genes[,1] pancreas_t2d=pancreas[index,] index=row.names(heart) %in% t2d_genes[,1] heart_t2d=heart[index,] index=row.names(muscle) %in% t2d_genes[,1] muscle_t2d=muscle[index,] index=row.names(blood) %in% t2d_genes[,1] blood_t2d=blood[index,] index=row.names(adipose) %in% t2d_genes[,1] adipose_t2d=adipose[index,] index=row.names(liver) %in% t2d_genes[,1] temp=liver[index,] liver_t2d <- aggregate(list(temp[,1:7]), by = list(row.names(temp)), median) rownames(liver_t2d)=liver_t2d[,1] liver_t2d=liver_t2d[-1]

##------#creating tissue table for pancrease #creating an empty table to store the range pancreas_table=matrix(ncol = 4, nrow = 574) row.names(pancreas_table)=row.names(pancreas_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in pancreas for(i in 1:nrow(pancreas_t2d)) { pancreas_table[i,1]=min(pancreas_t2d[i,]) pancreas_table[i,2]=max(pancreas_t2d[i,]) }

#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in pancreas library("matrixStats") pancreas_mean_sd=matrix(nrow = nrow(pancreas_t2d), ncol = 2) rownames(pancreas_mean_sd)=rownames(pancreas_t2d) colnames(pancreas_mean_sd)=c("mean", "SD") pancreas_mean_sd[,1]=rowMeans(pancreas_t2d) pancreas_mean_sd[,2]=rowSds(pancreas_t2d) pancreas_table[,3]=pancreas_mean_sd[,1]-(2.58*(pancreas_mean_sd[,2]/sqrt(61))) pancreas_table[,4]=pancreas_mean_sd[,1]+(2.58*(pancreas_mean_sd[,2]/sqrt(61)))

#assigning names to row and columns colnames(pancreas_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(pancreas_table)=row.names(pancreas_t2d)

#reading table containing complications associated with genes implicating complications in type 2 diabetes complications_t2d=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/complications.csv") row.names(complications_t2d)=complications_t2d[,1] complications_t2d=complications_t2d[-1]

#merging complications table and range table to create tissue table for pancreas pancreas_table= merge.default(pancreas_table, complications_t2d, by=0)

#creating table containing medians of expression value for each gene pancreas_median=as.matrix(rowMedians(pancreas_t2d)) rownames(pancreas_median)=row.names(pancreas_t2d) colnames(pancreas_median)="median"

#writing all the tables related to pancreas intro directory in csv format write.csv(pancreas_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_table.csv") write.csv(pancreas_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_controls.csv") write.csv(pancreas_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_mean_sd.csv") write.csv(pancreas_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_median.csv")

##------#creating tissue table for heart #creating an empty table to store the range heart_table=matrix(ncol = 4, nrow = 587) row.names(heart_table)=row.names(heart_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in heart for(i in 1:nrow(heart_t2d)) { heart_table[i,1]=min(heart_t2d[i,]) heart_table[i,2]=max(heart_t2d[i,]) }

##------#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in heart library("matrixStats") heart_mean_sd=matrix(nrow = nrow(heart_t2d), ncol = 2) rownames(heart_mean_sd)=rownames(heart_t2d) colnames(heart_mean_sd)=c("mean", "SD") heart_mean_sd[,1]=rowMeans(heart_t2d) heart_mean_sd[,2]=rowSds(heart_t2d) heart_table[,3]=heart_mean_sd[,1]-(2.58*(heart_mean_sd[,2]/sqrt(19))) heart_table[,4]=heart_mean_sd[,1]+(2.58*(heart_mean_sd[,2]/sqrt(19)))

#naming the rows and columns of the table colnames(heart_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(heart_table)=row.names(heart_t2d)

#reading file containing complications related to type 2 diabetes genes complications_t2d=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/complications.csv") row.names(complications_t2d)=complications_t2d[,1] complications_t2d=complications_t2d[-1]

#merging complications table and range table to create tissue table for heart heart_table= merge.default(heart_table, complications_t2d, by=0)

#creating a table containing median of gene expression values for heart heart_median=as.matrix(rowMedians(heart_t2d)) rownames(heart_median)=row.names(heart_t2d) colnames(heart_median)="median"

#writing all the tables related to heart intro directory in csv format write.csv(heart_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/heart_table.csv") write.csv(heart_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/heart_controls.csv") write.csv(heart_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/heart_mean_sd.csv") write.csv(heart_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/heart_median.csv")

##------#creating tissue table for muscle #creating an empty table to store the range muscle_table=matrix(ncol = 4, nrow = 525) row.names(muscle_table)=row.names(muscle_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in muscle for(i in 1:nrow(muscle_t2d)) { muscle_table[i,1]=min(muscle_t2d[i,]) muscle_table[i,2]=max(muscle_t2d[i,]) }

#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in muscle library("matrixStats") muscle_mean_sd=matrix(nrow = nrow(muscle_t2d), ncol = 2) rownames(muscle_mean_sd)=rownames(muscle_t2d) colnames(muscle_mean_sd)=c("mean", "SD") muscle_mean_sd[,1]=rowMeans(muscle_t2d) muscle_mean_sd[,2]=rowSds(muscle_t2d) muscle_table[,3]=muscle_mean_sd[,1]-(2.58*(muscle_mean_sd[,2]/sqrt(47))) muscle_table[,4]=muscle_mean_sd[,1]+(2.58*(muscle_mean_sd[,2]/sqrt(47)))

#naming the rows and columns of the table colnames(muscle_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(muscle_table)=row.names(muscle_t2d)

#merging complications table and range table to create tissue table for muscle

52 muscle_table= merge.default(muscle_table, complications_t2d, by=0)

#creating a table containing median of gene expression values for muscle muscle_median=as.matrix(rowMedians(muscle_t2d)) rownames(muscle_median)=row.names(muscle_t2d) colnames(muscle_median)="median"

#writing all the tables related to muscle intro directory in csv format write.csv(muscle_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_table.csv") write.csv(muscle_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_controls.csv") write.csv(muscle_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_mean_sd.csv") write.csv(muscle_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_median.csv")

##------#creating tissue table for blood #creating an empty table to store the range blood_table=matrix(ncol = 4, nrow = 525) row.names(blood_table)=row.names(blood_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in blood for(i in 1:nrow(blood_t2d)) { blood_table[i,1]=min(blood_t2d[i,]) blood_table[i,2]=max(blood_t2d[i,]) }

#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in blood library("matrixStats") blood_mean_sd=matrix(nrow = nrow(blood_t2d), ncol = 2) rownames(blood_mean_sd)=rownames(blood_t2d) colnames(blood_mean_sd)=c("mean", "SD") blood_mean_sd[,1]=rowMeans(blood_t2d) blood_mean_sd[,2]=rowSds(blood_t2d) blood_table[,3]=blood_mean_sd[,1]-(2.58*(blood_mean_sd[,2]/sqrt(30))) blood_table[,4]=blood_mean_sd[,1]+(2.58*(blood_mean_sd[,2]/sqrt(30)))

#naming the rows and columns of the table colnames(blood_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(blood_table)=row.names(blood_t2d)

#merging complications table and range table to create tissue table for blood blood_table= merge.default(blood_table, complications_t2d, by=0)

#creating a table containing median of gene expression values for blood blood_median=as.matrix(rowMedians(blood_t2d)) rownames(blood_median)=row.names(blood_t2d) colnames(blood_median)="median"

#writing all the tables related to blood intro directory in csv format write.csv(blood_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/blood_table.csv") write.csv(blood_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/blood_controls.csv") write.csv(blood_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/blood_mean_sd.csv") write.csv(blood_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/blood_median.csv")

##------#creating tissue table for adipose #creating an empty table to store the range adipose_table=matrix(ncol = 4, nrow = 556) row.names(adipose_table)=row.names(adipose_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in adipose for(i in 1:nrow(adipose_t2d)) { adipose_table[i,1]=min(adipose_t2d[i,]) adipose_table[i,2]=max(adipose_t2d[i,]) }

#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in adipose library("matrixStats") adipose_mean_sd=matrix(nrow = nrow(adipose_t2d), ncol = 2)

53 rownames(adipose_mean_sd)=rownames(adipose_t2d) colnames(adipose_mean_sd)=c("mean", "SD") adipose_mean_sd[,1]=rowMeans(adipose_t2d) adipose_mean_sd[,2]=rowSds(adipose_t2d) adipose_table[,3]=adipose_mean_sd[,1]-(2.58*(adipose_mean_sd[,2]/sqrt(11))) adipose_table[,4]=adipose_mean_sd[,1]+(2.58*(adipose_mean_sd[,2]/sqrt(11)))

#naming the rows and columns of the table colnames(adipose_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(adipose_table)=row.names(adipose_t2d)

#merging complications table and range table to create tissue table for adipose adipose_table= merge.default(adipose_table, complications_t2d, by=0)

#creating a table containing median of gene expression values for adipose adipose_median=as.matrix(rowMedians(adipose_t2d)) rownames(adipose_median)=row.names(adipose_t2d) colnames(adipose_median)="median"

#writing all the tables related to adipose intro directory in csv format write.csv(adipose_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_table.csv") write.csv(adipose_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_controls.csv") write.csv(adipose_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_mean_sd.csv") write.csv(adipose_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_median.csv")

##------#creating tissue table for liver #creating an empty table to store the range liver_table=matrix(ncol = 4, nrow = 636) row.names(liver_table)=row.names(liver_t2d)

#getting the actual range for genes implicating complications in type 2 diabetes in liver for(i in 1:nrow(liver_t2d)) { liver_table[i,1]=min(liver_t2d[i,]) liver_table[i,2]=max(liver_t2d[i,]) }

#getting the 99% confidence interval range for genes implicating complications in type 2 diabetes in liver library("matrixStats") liver_mean_sd=matrix(nrow = nrow(liver_t2d), ncol = 2) rownames(liver_mean_sd)=rownames(liver_t2d) colnames(liver_mean_sd)=c("mean", "SD") liver_mean_sd[,1]=rowMeans(liver_t2d) liver_mean_sd[,2]=rowSds(as.matrix(liver_t2d)) liver_table[,3]=liver_mean_sd[,1]-(2.58*(liver_mean_sd[,2]/sqrt(7))) liver_table[,4]=liver_mean_sd[,1]+(2.58*(liver_mean_sd[,2]/sqrt(7)))

#naming the rows and columns of the table colnames(liver_table)=c("Actual Min", "Actual Max", "99% CI Min", "99% CI Max") row.names(liver_table)=row.names(liver_t2d)

#merging complications table and range table to create tissue table for liver liver_table= merge.default(liver_table, complications_t2d, by=0)

#creating a table containing median of gene expression values for liver liver_median=as.matrix(rowMedians(as.matrix(liver_t2d))) rownames(liver_median)=row.names(liver_t2d) colnames(liver_median)="median"

#writing all the tables related to liver intro directory in csv format write.csv(liver_table, "C:/xampp/htdocs/T2DiGER/uploaded_files/liver_table.csv") write.csv(liver_t2d, "C:/xampp/htdocs/T2DiGER/uploaded_files/liver_controls.csv") write.csv(liver_mean_sd, "C:/xampp/htdocs/T2DiGER/uploaded_files/liver_mean_sd.csv") write.csv(liver_median, "C:/xampp/htdocs/T2DiGER/uploaded_files/liver_median.csv")

R Scripts to get Gene Expression Report for T2DiGER

# getting user input for tissue selection from command line args <- commandArgs(TRUE) n <- args[1]

# reading the userinput csv file containing gene expression data user_input=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/myfile.csv")

# generating gene expression report for desired tissue # n=1 is for pancreas if (n==1) {

# reading tissue table for pancreas final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_table.csv")

#reading containing median of normal gene expression values in pancreatic tissue control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/pancreas_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

#aggregating mutilipe expression value for same gene into median of all the values input_filter <- aggregate(list(input_filter[,2]), by = list(input_filter[,1]), median) colnames(input_filter)=c("genes","values") row.names(input_filter)=input_filter[,1] input_filter=input_filter[-1]

row.names(control_median)=control_median[,1] control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2] final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]=as.character(final_table_merge[i,8]) output_table[i,10]=as.character(final_table_merge[i,9]) output_table[i,11]=as.character(final_table_merge[i,10]) output_table[i,12]=as.character(final_table_merge[i,11]) output_table[i,13]=as.character(final_table_merge[i,12]) } else { output_table[i,1]=final_table_merge[i,1] output_table[i,2]="in normal range" output_table[i,3]=final_table_merge[i,2] output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]="-" output_table[i,10]="-" output_table[i,11]="-" output_table[i,12]="-" output_table[i,13]="-" } }

# assigning columns to the output table colnames(output_table)=c("Genes", "Remarks", "Your Exp Value", "Minimum Value", "Maximum Value", "99% CI Minimum Value", "99% CI Maximum Value", "Cardiovascular diseases","Retinopathy","Atherosclerosis","Nephropathy","Neuropathy", "link for reference")

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

}else if (n==2){

# reading tissue table for heart final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/heart_table.csv")

# reading table containing median of expression values for heart control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/heart_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

row.names(control_median)=control_median[,1] control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2]

final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

# creating output table which will display gene expression report output_table=matrix(nrow = nrow(input_norm), ncol = 13) for(i in 1:nrow(final_table_merge)) { # comparing normalized user input values with actual range if((final_table_merge[i,2] < final_table_merge[i,3])|(final_table_merge[i,2] > final_table_merge[i,4])) { output_table[i,1]=final_table_merge[i,1] output_table[i,2]="not in normal range" output_table[i,3]=final_table_merge[i,2] output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]=as.character(final_table_merge[i,8]) output_table[i,10]=as.character(final_table_merge[i,9]) output_table[i,11]=as.character(final_table_merge[i,10]) output_table[i,12]=as.character(final_table_merge[i,11]) output_table[i,13]=as.character(final_table_merge[i,12]) } else { output_table[i,1]=final_table_merge[i,1] output_table[i,2]="in normal range" output_table[i,3]=final_table_merge[i,2] output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]="-" output_table[i,10]="-" output_table[i,11]="-" output_table[i,12]="-" output_table[i,13]="-" } }

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

}else if (n==3){

# reading tissue table for muscle final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_table.csv")

# reading table containing median of expression values for muscle control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/muscle_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

row.names(control_median)=control_median[,1]

control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2] final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

}else if (n==4){ # reading tissue table for blood final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/blood_table.csv")

# reading table containing median of expression values for blood control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/blood_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

row.names(control_median)=control_median[,1] control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2] final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]="-" output_table[i,10]="-" output_table[i,11]="-" output_table[i,12]="-" output_table[i,13]="-" } }

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

}else if (n==5){

# reading tissue table for adipose final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_table.csv")

# reading table containing median of expression values for adipose control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/adipose_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

row.names(control_median)=control_median[,1] control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2] final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

output_table[i,1]=final_table_merge[i,1] output_table[i,2]="not in normal range" output_table[i,3]=final_table_merge[i,2] output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]=as.character(final_table_merge[i,8]) output_table[i,10]=as.character(final_table_merge[i,9]) output_table[i,11]=as.character(final_table_merge[i,10]) output_table[i,12]=as.character(final_table_merge[i,11]) output_table[i,13]=as.character(final_table_merge[i,12]) } else { output_table[i,1]=final_table_merge[i,1] output_table[i,2]="in normal range" output_table[i,3]=final_table_merge[i,2] output_table[i,4]=final_table_merge[i,3] output_table[i,5]=final_table_merge[i,4] output_table[i,6]=(final_table_merge[i,5]) output_table[i,7]=(final_table_merge[i,6]) output_table[i,8]=(final_table_merge[i,7]) output_table[i,9]="-" output_table[i,10]="-" output_table[i,11]="-" output_table[i,12]="-" output_table[i,13]="-" } }

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

}else if (n==6){

# reading tissue table for liver final_table=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/liver_table.csv") # reading table containing median of expression vaues for liver control_median=read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/liver_median.csv")

# filtering genes that implicate complication in type 2 diabetes from the median table index=user_input[,1] %in% control_median[,1] input_filter=user_input[index,]

row.names(control_median)=control_median[,1] control_median=control_median[-1]

# merging user input table and median table input_merge=merge(input_filter, control_median, by=0, all.x = TRUE)

#assigning row names to the merged table row.names(input_merge)=input_merge[,1] input_merge=input_merge[-1]

# library for quantile normalization library("preprocessCore")

# normalizing the user input wrt median of gene expression values of control samples input_merge_norm=normalize.quantiles(as.matrix(input_merge)) row.names(input_merge_norm)=row.names(input_merge)

input_norm=as.matrix(input_merge_norm[,1])

row.names(final_table)=final_table[,2] final_table=final_table[-1] final_table=final_table[-1]

#merging the tissue table and the table containing normalized user values final_table_merge=merge(input_norm, final_table, by=0)

# reducing all the expression values upto two poins after decimal final_table_merge[,2:6]=format(round(final_table_merge[,2:6], 2), nsmall = 2)

# writing output table in desired directory write.csv(output_table,"C:/xampp/htdocs/T2DiGER/output_table.csv")

R Script to match probe ids to gene names

# getting input for desired microarray platformfrom the command line args <- commandArgs(TRUE) n <- args[1]

# reading user input csv file containing list of probe ids input_table= read.csv("C:/xampp/htdocs/T2DiGER/uploaded_files/mymap.csv")

# getting gene names from desired microarray platform if (n==1) {

library("hgu133a.db") name_hgnc=select(hgu133a.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==2) { library("hgu133plus2.db") name_hgnc=select(hgu133plus2.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==3) { library("hgu95av2.db") name_hgnc=select(hgu95av2.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==4) { library("hgug4112a.db") name_hgnc=select(hgug4112a.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==5) { library("hugene10sttranscriptcluster.db") name_hgnc=select(hugene10sttranscriptcluster.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==6) { library("illuminaHumanv3.db") name_hgnc=select(illuminaHumanv3.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==7) { library("illuminaHumanv4.db") name_hgnc=select(illuminaHumanv4.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==8) { library("u133x3p.db") name_hgnc=select(u133x3p.db, as.matrix(input_table[,1]), c("SYMBOL")) }else if (n==9) { library("hgu133a2.db") name_hgnc=select(hgu133a2.db, as.matrix(input_table[,1]), c("SYMBOL")) }

# writing the result into csv file write.csv(name_hgnc, "C:/xampp/htdocs/T2DiGER/name_hgnc.csv")

Table A.1: table for adipose tissue

12 ADAM1 2.615115 4.637126 2.92341 3.845718 NA NA NA Nephropathy NA 0 13 ADAM1 3.174223 4.642063 3.739089 4.351428 NA NA Atherosclerosi Nephropathy NA 7 s 14 ADAMT 1.568961 2.777081 1.973998 2.574537 NA NA NA Nephropathy NA S13 15 ADCYA 1.572752 4.317269 1.796049 3.506984 NA Retinopathy NA Nephropathy NA P1 16 ADH1B 7.335053 8.472716 7.738942 8.369671 NA NA NA Nephropathy Neuropathy

17 ADIPO 4.587547 7.43608 5.470476 6.990465 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy Q diseases s 18 ADIPO 4.477439 5.913804 4.98963 5.668727 Cardiovascular NA NA NA NA R1 diseases 19 ADK 3.12809 4.240123 3.449836 4.006637 NA Retinopathy NA NA NA

20 ADM 5.888604 8.216695 6.691429 7.703543 NA Retinopathy NA Nephropathy Neuropathy

21 ADRA2 1.665912 2.731721 1.934577 2.524535 NA NA NA NA Neuropathy B 22 AGER 0.241068 2.404559 0.573168 1.577181 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s

23 AGT 2.701131 4.609208 2.842556 3.665517 NA NA NA Nephropathy Neuropathy

24 AGTR1 4.392137 7.200829 4.940508 6.117186 NA NA NA Nephropathy NA

25 AGXT2 0.974116 4.293639 1.29817 2.690401 Cardiovascular NA NA NA NA diseases 26 AHSA1 4.319574 5.322668 4.720311 5.16447 Cardiovascular Retinopathy NA Nephropathy NA diseases 27 AHSG 0.663649 2.373369 0.875476 1.640291 Cardiovascular Retinopathy NA Nephropathy NA diseases 28 AKR1B1 4.723601 6.471134 5.147343 5.852261 NA Retinopathy NA Nephropathy Neuropathy

29 AKR1B1 1.416283 2.529933 1.806637 2.349889 NA NA NA Nephropathy NA 0 30 AKT1 3.82416 4.870625 3.878253 4.377253 Cardiovascular Retinopathy NA Nephropathy NA diseases 31 ALB 0.802001 2.785368 1.102734 1.875188 NA NA Atherosclerosi Nephropathy Neuropathy s 32 ALDH1 5.642223 8.329221 6.342063 7.675462 NA NA NA Nephropathy NA A1 33 ALDH2 7.642818 9.668575 8.124224 9.029273 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 34 ALOX5 4.750239 6.256804 5.058014 5.868831 NA NA Atherosclerosi Nephropathy NA AP s 35 ALPK1 2.043025 2.91985 2.297578 2.752988 Cardiovascular NA NA NA NA diseases 36 ALPL 2.034617 3.767996 2.267623 3.078082 NA NA NA Nephropathy NA

37 AMBP 0.738635 2.892835 1.287467 2.198783 NA NA NA Nephropathy NA

38 ANG 4.485917 6.780353 4.72823 5.805955 NA NA NA Nephropathy NA

39 ANGPT 3.299105 5.302025 3.455667 4.329073 NA Retinopathy NA NA NA 2 40 ANGPT 4.192524 6.388006 4.550257 5.398187 NA NA Atherosclerosi Nephropathy NA L2 s 41 ANGPT 0.676559 4.127386 2.39866 3.84226 NA Retinopathy NA Nephropathy NA L4 42 AOC2 3.581595 4.50534 3.815057 4.250403 NA NA NA Nephropathy NA

43 AOC3 4.882972 6.510216 5.228284 6.077203 NA Retinopathy NA NA NA

44 APC 3.187253 3.74272 3.328056 3.628257 NA NA NA Nephropathy NA

45 API5 4.01352 5.596059 4.147155 4.959034 NA Retinopathy NA NA NA

46 APLN 2.377739 3.458423 2.627484 3.153243 NA NA NA NA Neuropathy

47 APOA5 0.878403 2.423023 1.218234 1.91794 Cardiovascular NA Atherosclerosi NA NA diseases s 48 APOB 1.910381 3.856588 2.21914 3.060598 Cardiovascular Retinopathy NA NA Neuropathy diseases 49 APOC1 3.832148 6.588739 4.261328 5.658299 NA NA NA Nephropathy NA

50 APOE 1.017066 6.475811 2.839382 6.031071 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 51 APOH 1.13058 1.88651 1.427927 1.749918 Cardiovascular NA NA NA NA diseases 52 APOL1 1.232568 4.026799 2.548352 3.827638 Cardiovascular NA NA Nephropathy NA diseases 53 APOM 1.277313 2.453099 1.62114 2.193376 NA NA Atherosclerosi NA NA s 54 AQP1 2.138711 5.805626 3.174138 5.0054 NA Retinopathy NA NA NA

55 AQP4 0.761256 2.344558 1.113503 1.894429 NA Retinopathy NA NA NA

56 AQP5 2.587615 3.614702 2.862632 3.339129 NA NA NA Nephropathy NA

57 AR 2.539918 3.936015 2.752065 3.492476 NA NA NA Nephropathy NA

58 ASPA 1.790784 3.338845 2.438204 3.10653 NA NA NA NA Neuropathy

59 ATF4 6.900262 8.594155 7.627761 8.433751 NA Retinopathy NA Nephropathy NA

60 ATM 1.409176 2.870186 1.892108 2.467596 Cardiovascular NA NA NA NA diseases 61 ATP2A2 3.174381 5.612893 3.631932 4.663034 NA NA NA NA Neuropathy

62 B2M 8.439142 9.850025 8.954815 9.653389 NA NA Atherosclerosi Nephropathy NA s 63 BAAT 0.320378 2.699589 0.654351 1.703607 NA NA Atherosclerosi NA NA s 64 BAMBI 2.714436 4.140587 3.004087 3.639062 NA NA NA Nephropathy NA

65 BASP1 5.410706 6.853763 5.810092 6.566804 NA NA NA Nephropathy NA

66 BCL2 2.174588 4.33954 2.647961 3.612989 NA NA NA Nephropathy NA

67 BDKRB 2.681697 6.494075 2.55651 4.224412 NA NA NA NA Neuropathy 1 68 BDKRB 1.869214 3.277243 2.170049 2.806774 NA NA NA NA Neuropathy 2 69 BDNF 1.156081 2.863651 1.606385 2.436661 NA Retinopathy NA NA Neuropathy

70 BMP2 2.393855 5.81341 3.01119 4.420583 NA NA Atherosclerosi NA NA s 71 BMP4 2.875428 3.933713 3.141362 3.659827 NA NA NA Nephropathy NA

72 BNIP3 4.59781 5.651558 4.870614 5.327053 Cardiovascular NA NA NA NA diseases 73 C5 2.118816 3.296356 2.571142 3.07526 NA Retinopathy NA Nephropathy NA

74 CACNA 1.088305 2.076579 1.166298 1.603149 NA NA NA NA Neuropathy 1H 75 CAPN10 1.383902 2.34882 1.719037 2.216162 NA NA Atherosclerosi NA NA s 76 CARM1 2.185682 4.024356 2.739022 3.456729 NA NA NA Nephropathy NA

77 CAT 5.153669 7.589303 5.944048 7.191892 NA Retinopathy NA Nephropathy NA

78 CAV1 5.735933 8.155166 6.173192 7.262112 NA NA NA Nephropathy Neuropathy

79 CCK 2.028088 2.882627 2.227463 2.692575 NA NA NA Nephropathy Neuropathy

80 CCKAR 1.198061 2.244563 1.46944 1.914373 NA NA NA Nephropathy NA

81 CCL2 5.580628 8.556274 6.36555 7.861281 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 82 CCL20 0.486662 4.400271 1.396584 3.036521 NA NA NA Nephropathy NA

83 CCL5 4.214495 5.506897 4.470083 5.180403 NA NA NA Nephropathy NA

84 CCR1 2.678779 5.308778 3.699117 5.000352 NA NA NA Nephropathy NA

85 CCR2 0.973497 2.569496 1.254996 2.011576 NA NA Atherosclerosi Nephropathy NA s 86 CCR5 2.564016 4.063529 3.051509 3.878473 NA NA Atherosclerosi Nephropathy NA s 87 CD160 0.933797 3.076311 1.456032 2.404264 NA Retinopathy NA NA NA

88 CD163 6.271543 8.420905 6.96388 8.0942 NA Retinopathy Atherosclerosi NA Neuropathy s 89 CD2AP 2.684217 4.152053 2.972471 3.653559 NA NA NA Nephropathy NA

90 CD34 3.913511 4.921218 4.158035 4.766828 NA NA NA NA Neuropathy

91 CD36 5.427409 6.91831 5.730163 6.587724 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 92 CD38 1.59009 4.041254 2.152473 3.212057 NA NA NA Nephropathy NA

93 CD4 1.173255 3.179124 1.710199 2.770257 Cardiovascular NA Atherosclerosi NA NA diseases s 94 CD40 1.468503 3.739921 2.422016 3.336538 Cardiovascular NA Atherosclerosi NA NA diseases s 95 CD40L 1.638459 3.083313 1.938862 2.609978 Cardiovascular NA NA Nephropathy NA G diseases 96 CD47 4.031244 5.751616 4.592466 5.417773 NA NA NA Nephropathy NA

97 CD59 5.965605 7.037446 6.13591 6.64413 NA Retinopathy NA NA NA

98 CD63 7.944335 9.133905 8.234515 8.786053 NA NA NA Nephropathy NA

99 CD68 5.66697 7.322033 6.116742 6.854885 NA NA NA Nephropathy NA

100 CD69 2.625192 6.139181 3.631435 5.046113 NA NA NA Nephropathy NA

101 CD74 6.69852 8.593698 7.189455 8.107524 NA NA NA Nephropathy NA

102 CD80 0.999686 2.099066 1.163841 1.766998 NA NA NA Nephropathy NA

103 CD9 4.578643 5.567046 4.929283 5.381576 Cardiovascular NA NA NA NA diseases 104 CDH1 1.20301 4.408748 1.610504 3.193034 NA NA NA Nephropathy NA

105 CDH2 0.772238 2.797413 1.196405 2.329627 NA NA NA Nephropathy NA

106 CDK7 3.334069 4.565461 3.569463 4.172071 NA NA NA Nephropathy NA

107 CDKAL 1.59825 3.601533 2.126725 3.182168 Cardiovascular NA NA Nephropathy NA 1 diseases 108 CDKN1 5.018858 8.576197 5.768319 7.280986 NA NA NA Nephropathy NA A 109 CDKN2 1.596405 2.764347 2.047034 2.630981 Cardiovascular NA NA NA NA A diseases 110 CETP 1.507248 3.010611 2.011329 2.626214 Cardiovascular NA Atherosclerosi NA NA diseases s

111 CHI3L1 2.081831 4.713609 2.841815 3.998755 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 112 CHIT1 0.820304 2.375453 1.240888 2.00619 NA NA NA Nephropathy NA

113 CHN2 1.271475 3.349483 1.799404 2.582152 NA Retinopathy NA Nephropathy NA

114 CHPT1 3.621672 5.477118 4.494252 5.305089 NA NA NA Nephropathy NA

115 CISH 1.801521 4.218278 2.410426 3.347905 NA NA NA Nephropathy NA

116 CITED2 4.276073 5.671536 4.567572 5.33039 NA NA Atherosclerosi NA NA s 117 CLCN5 2.439303 4.131782 2.899583 3.751377 NA NA NA Nephropathy NA

118 CLEC11 2.629061 3.468374 2.915149 3.337999 NA NA NA Nephropathy NA A 119 CLOCK 3.901822 4.507045 3.967879 4.302199 Cardiovascular NA NA NA NA diseases 120 CMA1 3.537364 4.355211 3.751521 4.146602 NA NA NA Nephropathy NA

121 CNDP1 1.306533 2.294364 1.527214 1.997076 Cardiovascular NA NA Nephropathy NA diseases 122 CNDP2 5.041993 6.590456 5.596278 6.389166 NA NA NA Nephropathy NA

123 CNR1 1.137058 2.18897 1.177439 1.714549 NA Retinopathy NA Nephropathy Neuropathy

124 CNR2 1.694877 2.96626 2.228644 2.788173 NA NA NA Nephropathy Neuropathy

125 COG2 3.565905 4.623646 3.826664 4.298725 NA NA Atherosclerosi NA NA s 126 COL8A1 3.776157 6.548997 4.66306 5.986353 NA NA NA Nephropathy NA

127 COL8A2 1.700704 2.657938 1.817373 2.373908 NA NA NA Nephropathy NA

128 COLEC 5.161827 6.870949 5.687334 6.409865 NA Retinopathy NA NA NA 12 129 COMT 4.352724 5.184789 4.669763 5.050866 Cardiovascular NA NA NA NA diseases 130 CPVL 4.682806 7.233608 5.610215 6.766314 NA NA NA Nephropathy NA

131 CRH 0.576122 2.804622 1.312842 2.300377 NA NA NA NA Neuropathy

132 CRK 3.130959 4.786233 3.358671 4.116237 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 133 CRP 1.42152 2.526868 1.791632 2.302035 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 134 CST3 7.383076 8.399341 7.658384 8.190208 Cardiovascular NA NA NA NA diseases 135 CTGF 5.325281 7.129012 5.685977 6.544687 NA Retinopathy NA Nephropathy NA

136 CTSH 4.762992 6.805478 5.44989 6.517873 NA Retinopathy NA NA NA

137 CTSS 4.253165 6.336438 4.948152 5.807033 Cardiovascular NA NA NA NA diseases 138 CUBN 1.585059 2.393977 1.772287 2.191988 NA NA NA Nephropathy NA

139 CX3CL1 3.655513 5.638401 4.082219 4.896928 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 140 CX3CR1 2.779459 3.859793 2.964794 3.540296 NA NA NA Nephropathy NA

141 CXCL10 1.352142 4.073788 2.03232 3.439041 NA NA NA Nephropathy Neuropathy

142 CXCL11 0.174099 3.372108 1.152685 2.540449 NA NA NA Nephropathy NA

143 CXCL12 5.239254 8.332603 5.695751 7.291436 NA NA NA Nephropathy NA

144 CXCL16 3.05489 5.265154 3.5987 4.709852 NA NA NA Nephropathy NA

145 CXCL5 0.710993 3.449207 0.970345 2.385323 NA NA Atherosclerosi Nephropathy NA s 146 CXCL9 0.779529 4.255963 1.623676 2.9312 NA NA NA Nephropathy NA

147 CYBA 4.609106 5.867708 4.85222 5.45373 NA NA Atherosclerosi Nephropathy NA s 148 CYBB 4.929051 6.854714 5.2447 6.326675 NA Retinopathy NA NA NA

149 CYP1A1 0.860093 4.087652 1.299098 2.97334 Cardiovascular NA Atherosclerosi NA NA diseases s 150 CYP24A 0.221673 2.038924 0.720345 1.547115 NA NA NA Nephropathy NA 1 151 CYP2C1 1.530963 2.51556 1.882917 2.418855 NA Retinopathy NA NA NA 9 152 CYP2J2 1.759035 3.762666 2.290132 3.297998 Cardiovascular NA NA Nephropathy NA diseases 153 CYP7A1 1.41816 3.264409 1.869798 2.72353 Cardiovascular NA NA NA NA diseases 154 CYR61 5.286508 8.079318 6.569428 7.745363 NA Retinopathy NA NA NA

155 DCXR 4.711772 6.018438 5.000664 5.625063 NA NA NA Nephropathy NA

156 DDAH1 1.23666 2.748117 1.442392 2.228623 NA Retinopathy NA Nephropathy NA

157 DDIT3 3.571395 5.168569 3.97138 4.686804 Cardiovascular NA NA Nephropathy Neuropathy diseases 158 DES 3.012085 3.826815 3.094461 3.468028 NA NA NA Nephropathy NA

159 DGKH 0.276527 1.824871 0.926017 1.703964 NA NA NA Nephropathy NA

160 DHCR7 2.384863 3.314381 2.373786 2.918208 NA NA Atherosclerosi NA NA s 161 DKK1 1.215869 3.973967 1.419657 2.560336 Cardiovascular Retinopathy NA Nephropathy NA diseases 162 DNMT1 3.165373 4.162176 3.400833 3.93147 NA NA NA Nephropathy NA

163 DPP4 3.212419 5.570002 3.950038 5.013566 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 164 EBF2 1.989226 4.146845 2.684249 3.782221 NA NA NA Nephropathy NA

165 EDN1 1.448424 3.388737 1.942382 2.76322 NA Retinopathy NA Nephropathy Neuropathy

166 EDNRA 4.091267 5.386285 4.299244 4.948503 NA NA NA Nephropathy NA

167 EGF 0.381706 2.024352 0.736843 1.550225 NA NA NA Nephropathy NA

168 EGFR 3.12362 4.448786 3.623214 4.264976 Cardiovascular NA NA Nephropathy NA diseases 169 EIF2AK 3.65212 4.510141 3.740815 4.122071 NA NA NA Nephropathy NA 3 170 EIF4EB 3.742398 4.624627 4.08086 4.511054 NA NA NA Nephropathy NA P1 171 ELMO1 1.273025 4.237767 1.542025 2.79413 NA NA NA Nephropathy NA

172 ELN 1.925021 3.59515 2.265399 2.957976 NA NA Atherosclerosi NA NA s 173 ENG 2.531099 4.50519 2.869048 3.812177 Cardiovascular Retinopathy NA NA Neuropathy diseases 174 ENPP1 2.146051 4.128375 2.738479 3.702058 NA NA NA Nephropathy NA

175 ENPP2 4.389802 6.153334 4.958689 5.751245 NA NA NA NA Neuropathy

176 ENTPD 2.260752 3.405058 2.669954 3.224785 NA NA Atherosclerosi Nephropathy NA 1 s 177 EPO 0.661676 2.172047 1.162668 1.917583 NA Retinopathy NA Nephropathy Neuropathy

178 EPOR 2.300438 2.974576 2.441428 2.788444 NA NA NA Nephropathy NA

179 ERBB2 3.412574 4.502365 3.586937 4.04043 Cardiovascular NA NA NA Neuropathy diseases 180 ERBB3 0.97992 3.084625 1.346808 2.36242 NA Retinopathy NA NA NA

181 ERBB4 1.167674 1.911793 1.359891 1.772003 NA NA NA Nephropathy NA

182 ERCC1 3.828913 4.443665 4.003278 4.336781 NA Retinopathy NA Nephropathy NA

183 ERCC4 1.000495 2.321655 1.329568 1.907646 NA Retinopathy NA Nephropathy NA

184 ESAM 1.76299 4.311897 2.14414 3.377025 NA NA NA Nephropathy NA

185 ESM1 0.974977 3.48426 1.444355 2.441377 NA NA NA NA Neuropathy

186 ESR1 3.018692 4.037341 3.34343 3.757812 NA NA NA Nephropathy NA

187 EXOSC 4.744828 5.528143 4.931546 5.280432 NA NA NA Nephropathy NA 7 188 F11 0.067383 2.190351 0.628296 1.467397 NA NA NA Nephropathy NA

189 F2R 0.645283 2.527548 1.275163 2.248977 NA NA NA Nephropathy NA

190 F8 3.745133 4.532326 3.911999 4.284666 NA NA NA NA Neuropathy

191 FABP1 1.092876 1.939203 1.408776 1.867427 Cardiovascular NA NA Nephropathy NA diseases 192 FABP2 0.99929 2.076104 1.17174 1.699657 NA NA NA Nephropathy NA

193 FABP4 7.302556 8.985842 7.690675 8.658852 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 194 FABP5 6.238946 7.610923 6.493465 7.120033 Cardiovascular NA Atherosclerosi NA NA diseases s 195 FADS1 2.909582 5.659625 3.633833 4.933769 Cardiovascular NA NA NA NA diseases 196 FADS2 2.64622 4.058422 2.823383 3.422216 Cardiovascular NA NA NA NA diseases 197 FASN 1.44243 5.72019 2.991974 5.015983 NA NA NA Nephropathy NA

198 FBXO8 3.859533 4.519935 4.146199 4.442815 NA Retinopathy NA NA NA

199 FGF19 1.859561 3.729293 2.716559 3.531579 Cardiovascular NA NA NA NA diseases 200 FGF21 0.728723 2.460368 1.07936 1.81809 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 201 FGF23 0.607217 2.814506 1.258031 2.225759 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 202 FGFR1 1.820653 3.424914 2.491111 3.251873 NA NA Atherosclerosi NA NA s 203 FKBP10 2.465846 3.530814 2.967305 3.444424 Cardiovascular NA NA NA NA diseases 204 FKBP2 3.433765 4.876499 3.909438 4.569907 NA NA Atherosclerosi NA NA s 205 FKBP4 4.327561 4.926168 4.454357 4.755264 Cardiovascular NA NA NA NA diseases 206 FKBP8 2.860247 4.541959 3.56496 4.318742 Cardiovascular NA NA NA NA diseases 207 FMO3 3.246703 4.570152 3.605231 4.189935 NA NA Atherosclerosi NA NA s 208 FMOD 5.048513 5.796821 5.327525 5.668373 NA NA Atherosclerosi NA NA s 209 FN3K 0.832409 2.670888 1.412554 2.202896 NA NA NA Nephropathy NA

210 FOLH1 1.233684 2.433735 1.709501 2.311647 NA NA NA NA Neuropathy

211 FOS 5.40801 10.20611 7.353243 9.696479 NA NA NA Nephropathy NA

212 FOXA2 1.372076 2.630175 1.597499 2.256576 NA NA Atherosclerosi NA NA s 213 FPR1 2.90043 5.482641 3.395793 4.796676 NA NA Atherosclerosi NA NA s 214 FRMD3 1.932195 3.690452 2.105362 3.078632 NA Retinopathy NA Nephropathy NA

215 G6PD 2.551084 3.234765 2.767279 3.115212 Cardiovascular NA NA Nephropathy Neuropathy diseases 216 GAP43 1.61401 2.316145 1.7872 2.184905 NA NA NA NA Neuropathy

217 GAS1 7.549028 8.702067 7.98865 8.575655 NA NA NA Nephropathy NA

218 GAS6 1.787755 7.353801 3.310963 6.017063 NA NA NA Nephropathy NA

219 GCG 1.059282 2.970556 1.320845 2.228301 NA NA NA Nephropathy NA

220 GCK 1.198218 2.025415 1.429975 1.805535 NA NA NA Nephropathy Neuropathy

221 GCKR 0.586424 1.911827 1.003481 1.747542 Cardiovascular NA NA NA NA diseases 222 GDF15 0.831669 3.004141 1.809143 2.850273 Cardiovascular NA NA Nephropathy NA diseases 223 GDNF 0.761898 2.363707 0.885537 1.640451 NA Retinopathy NA NA Neuropathy

224 GFAP 1.540856 2.544864 1.73434 2.192112 NA NA NA NA Neuropathy

225 GFPT1 3.380956 4.702659 3.838825 4.391219 NA NA NA Nephropathy NA

226 GFPT2 5.562634 6.50259 5.654898 6.093574 NA NA NA Nephropathy NA

227 GHR 5.059877 7.176422 5.815406 6.834764 NA NA NA Nephropathy NA

228 GHRL 1.04335 2.764475 1.437679 2.263982 Cardiovascular NA NA Nephropathy NA diseases 229 GHSR 0.781397 2.597555 1.285591 2.081386 NA NA NA Nephropathy NA

230 GIP 0.841697 2.35033 1.051762 1.744365 Cardiovascular NA Atherosclerosi NA Neuropathy diseases s 231 GIPR 0.649804 1.954075 1.132277 1.723337 NA Retinopathy NA NA Neuropathy

232 GK 1.160796 2.977563 1.826183 2.557903 Cardiovascular NA NA NA NA diseases 233 GLO1 4.87353 5.711317 5.285928 5.6279 NA NA Atherosclerosi Nephropathy Neuropathy s 234 GLP1R 0.729133 2.209201 0.975424 1.671207 Cardiovascular NA NA NA Neuropathy diseases 235 GLUL 6.227364 7.561541 6.432722 7.019486 Cardiovascular NA NA NA NA diseases 236 GNB3 2.972861 4.037566 3.109799 3.662442 NA NA NA Nephropathy NA

237 GPC5 0.897812 2.339893 1.067709 1.655374 NA NA NA Nephropathy NA

238 GRB2 4.774685 5.822947 4.893134 5.376671 NA Retinopathy NA NA NA

239 GREM1 3.332493 6.116266 3.414226 4.884707 NA NA NA Nephropathy NA

240 GSTT1 2.566513 6.760336 4.352027 6.169347 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 241 GYS1 3.438526 4.267039 3.596795 4.040573 Cardiovascular NA NA NA NA diseases 242 HBG2 2.342988 6.846696 4.578427 6.509638 NA Retinopathy NA NA NA

243 HDAC4 3.491308 4.52892 3.848026 4.308217 NA NA NA Nephropathy NA

244 HDAC9 1.066406 2.094779 1.184886 1.690344 NA NA Atherosclerosi NA NA s 245 HFE 2.422233 3.33613 2.712834 3.224064 NA Retinopathy NA Nephropathy NA

246 HGF 0.564766 2.055384 0.829042 1.608945 NA NA Atherosclerosi Nephropathy Neuropathy s 247 HHEX 3.41549 4.349174 3.605053 4.058878 Cardiovascular NA NA Nephropathy NA diseases 248 HIF1A 3.198091 5.032364 3.354314 4.270203 Cardiovascular NA NA Nephropathy NA diseases 249 HLA- 5.00688 7.205032 5.360509 6.408975 NA NA NA Nephropathy NA DQA1 250 HMGA2 1.049323 2.510667 1.302061 1.964826 NA NA NA Nephropathy NA

251 HMGB1 5.3353 6.661533 5.592373 6.192272 Cardiovascular Retinopathy NA Nephropathy NA diseases 252 HMGCS 1.92103 2.720819 2.093011 2.483786 NA NA NA Nephropathy NA 2 253 HMOX1 3.768563 6.239249 4.077355 5.355003 NA NA NA Nephropathy NA

254 HNF4A 0.665006 2.450478 0.870311 1.63756 Cardiovascular NA NA NA NA diseases 255 HP 3.134199 8.6069 4.457956 6.924553 Cardiovascular NA Atherosclerosi NA NA diseases s 256 HPSE 0.965904 2.811935 1.551573 2.337043 NA NA NA Nephropathy NA

257 HRH1 2.932798 3.826713 3.170963 3.538615 NA NA NA NA Neuropathy

258 HRH2 1.450695 2.478695 1.671722 2.205159 NA NA NA NA Neuropathy

259 HS6ST3 0.97242 2.279756 1.44444 2.054403 NA Retinopathy NA NA NA

260 HSPA1A 7.405343 9.223591 7.694874 8.639988 NA NA NA Nephropathy NA

261 HSPA1B 6.649563 8.240868 6.915285 7.854784 NA NA NA Nephropathy NA

262 HSPA5 4.549427 5.790761 4.958797 5.545602 NA NA NA NA Neuropathy

263 HSPB1 6.612394 7.6991 6.901634 7.45788 NA NA NA Nephropathy NA

264 HSPG2 0.991572 2.627556 1.132937 1.98923 NA NA NA Nephropathy NA

265 HTR2A 1.404586 4.239224 1.708961 3.041105 NA NA NA Nephropathy NA

266 HYOU1 2.871922 4.191209 3.038074 3.611345 NA NA NA Nephropathy Neuropathy

267 ICAM1 2.364322 4.530081 2.790591 3.874647 NA NA Atherosclerosi Nephropathy NA s 268 ID1 4.735691 6.075538 4.981494 5.725923 NA NA NA Nephropathy NA

269 IFNG 1.893731 2.701532 2.084323 2.518722 NA NA NA Nephropathy Neuropathy

270 IGF1 5.495767 7.54561 5.660577 6.563186 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 271 IGF1R 1.251032 2.848947 1.567881 2.373241 NA Retinopathy NA NA NA

272 IGF2 2.528694 3.574686 2.753941 3.277157 NA Retinopathy NA Nephropathy Neuropathy

273 IGFBP1 1.080417 3.145429 1.739125 2.615663 NA NA NA Nephropathy NA

274 IGFBP5 4.470855 5.625546 4.913128 5.463969 NA NA NA NA Neuropathy

275 IGFBP7 7.085326 8.24568 7.234652 7.77174 NA NA NA Nephropathy NA

276 IL10 2.275491 3.747045 2.561829 3.206785 NA NA NA Nephropathy Neuropathy

277 IL18 6.09755 7.502726 6.469148 7.257795 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 278 IL1B 2.488675 6.794603 4.035257 5.713437 Cardiovascular Retinopathy NA Nephropathy NA diseases 279 IL1RN 0.816548 5.149904 1.355704 3.365731 NA NA NA Nephropathy NA

280 IL4 1.225222 2.558235 1.494601 2.063604 NA NA NA NA Neuropathy

281 IL6 1.838054 7.994305 3.193208 6.100162 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 282 ILK 4.609636 5.073209 4.691499 4.887799 NA NA NA Nephropathy NA

283 INS 1.913112 4.015625 2.464767 3.385487 Cardiovascular Retinopathy Atherosclerosi NA NA diseases s 284 IRAK1 -0.4052 4.057895 1.771073 3.715123 NA NA NA NA Neuropathy

285 IRAK4 2.143519 3.18698 2.46205 2.990377 NA NA Atherosclerosi NA NA s 286 IRS1 2.652649 3.91424 3.014215 3.589766 NA Retinopathy NA NA NA

287 IRS2 2.915724 4.117427 3.152567 3.673772 NA NA Atherosclerosi Nephropathy Neuropathy s 288 ITGA2 0.63223 2.435893 1.068239 1.945597 NA Retinopathy NA NA NA

289 ITGAM 3.221862 4.571802 3.674472 4.492997 NA Retinopathy NA Nephropathy NA

290 ITGB3 1.365914 2.942045 1.966032 2.670962 NA Retinopathy NA NA NA

291 JAK2 3.486764 4.465355 3.805587 4.229284 NA NA NA Nephropathy NA

292 JAZF1 2.424507 3.819562 2.953583 3.714443 Cardiovascular NA NA Nephropathy NA diseases 293 KCNJ11 1.700749 3.163279 2.358922 3.047486 NA Retinopathy NA NA Neuropathy

294 KCNQ1 0.990229 2.195288 1.40559 1.900761 NA NA NA Nephropathy NA

295 KL 2.698125 3.574868 2.942088 3.357907 NA NA NA Nephropathy NA

296 KLF10 3.926726 5.912276 4.496692 5.478362 NA NA NA Nephropathy NA

297 KLF6 3.832533 5.52717 4.307019 5.079517 NA NA NA Nephropathy NA

298 L1CAM 1.098601 2.618225 1.484511 2.059802 NA Retinopathy NA NA NA

299 LAMC1 5.75613 7.566788 5.952681 6.871448 NA NA NA Nephropathy NA

300 LAP3 4.963115 6.203416 5.127506 5.787602 NA NA NA Nephropathy NA

301 LDLR 2.851875 5.451909 3.56411 4.933737 Cardiovascular NA Atherosclerosi NA NA diseases s 302 LEP 1.099243 8.115188 3.097971 5.833572 NA NA Atherosclerosi NA Neuropathy s 303 LIMK2 3.118978 4.598085 3.396746 4.037919 NA NA NA Nephropathy NA

304 LMNA 3.020118 5.963782 3.732056 5.187978 NA NA NA Nephropathy NA

305 LPA 1.266105 2.449861 1.488303 2.121224 Cardiovascular NA Atherosclerosi NA NA diseases s 306 LPL 4.958388 7.266227 5.520487 6.620953 Cardiovascular NA Atherosclerosi Nephropathy Neuropathy diseases s 307 LPO 1.258138 2.873117 1.653843 2.340142 NA Retinopathy NA NA NA

308 LRP2 1.726018 5.203321 2.449597 3.935718 NA NA NA Nephropathy NA

309 LTA 1.675184 2.527191 1.904721 2.346817 NA NA NA Nephropathy NA

310 LTB4R2 1.922323 3.567037 2.339854 3.092351 NA Retinopathy NA NA NA

311 MAD2L 3.314107 4.074377 3.538323 3.906737 NA NA NA Nephropathy NA 2 312 MAFB 5.786355 7.646905 6.241352 7.098435 Cardiovascular NA Atherosclerosi NA NA diseases s 313 MALT1 1.102136 2.919243 1.609431 2.345904 NA NA NA Nephropathy NA

314 MAP3K 4.402391 5.572278 4.51644 5.120801 Cardiovascular NA NA Nephropathy NA 5 diseases 315 MAPK1 3.027304 4.052423 3.242261 3.767352 NA NA NA Nephropathy Neuropathy

316 MAPK1 2.326524 3.643718 2.426281 3.01491 NA NA NA Nephropathy NA 4 317 MAPK7 1.334456 2.74341 1.950781 2.514519 NA Retinopathy NA NA NA

318 MBL2 0.215465 2.308729 1.149107 2.10491 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 319 MBP 1.738641 3.226429 2.028016 2.703045 NA NA NA NA Neuropathy

320 MC4R 1.094589 4.148127 1.22179 2.497356 Cardiovascular NA NA Nephropathy NA diseases 321 MCAM 2.812807 4.213503 3.299992 3.954183 NA NA NA Nephropathy NA

322 MEP1B 0.823346 1.892227 1.209238 1.714921 NA NA NA Nephropathy NA

323 MIF 4.948291 6.83076 5.17966 5.993919 NA NA Atherosclerosi Nephropathy Neuropathy s 324 MME 3.8431 5.327549 4.338033 4.968195 NA NA NA NA Neuropathy

325 MMP14 2.230781 3.456549 2.753157 3.340618 NA NA NA Nephropathy NA

326 MMP16 1.117965 2.535724 1.209902 1.847352 NA NA NA Nephropathy NA

327 MMP2 4.087037 7.049159 4.485243 5.786571 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 328 MMP24 1.914597 2.621293 1.965617 2.343578 NA NA NA Nephropathy NA

329 MMP9 1.040343 2.786427 1.581524 2.458613 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 330 MPO 1.379379 2.680192 1.683911 2.203786 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s

331 MRPL2 3.545132 4.187036 3.730646 4.059224 NA Retinopathy NA NA NA 8 332 MSH2 3.459033 4.249359 3.634024 3.999938 Cardiovascular NA NA NA NA diseases 333 MT1A 5.925864 8.924863 6.66092 8.192186 Cardiovascular NA NA NA Neuropathy diseases 334 MTHFD 1.854056 3.205593 2.147616 2.800655 Cardiovascular NA NA NA NA 1L diseases 335 MTHFR 1.701178 2.60292 1.927632 2.395263 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 336 MYD88 1.844733 2.924204 2.026574 2.553279 NA NA NA Nephropathy NA

337 MYH9 2.373108 5.127963 3.145905 4.616785 NA NA NA Nephropathy NA

338 MYO5C 1.868377 3.169928 2.103579 2.824551 NA Retinopathy NA NA NA

339 NAGLU 3.189683 4.271698 3.411809 3.991128 Cardiovascular Retinopathy NA NA NA diseases 340 NCALD 2.82407 4.229437 3.146229 3.820289 NA NA NA Nephropathy NA

341 NCF1 3.3509 5.286721 3.613683 4.489655 NA NA NA Nephropathy NA

342 NCF2 3.848931 6.472684 5.025864 6.110471 NA NA NA Nephropathy NA

343 NDUFS 5.329364 6.296609 5.729494 6.156126 NA NA NA Nephropathy NA 3 344 NEDD4 2.832799 3.741097 3.060019 3.526585 NA NA NA Nephropathy NA L 345 NFE2 1.811183 5.224117 2.184462 3.768946 NA NA NA Nephropathy NA

346 NFE2L2 4.808014 5.802894 5.097577 5.569025 NA Retinopathy NA Nephropathy Neuropathy

347 NFKBIA 6.530372 8.507268 6.957231 7.937936 NA NA NA Nephropathy NA

348 NGB 1.894717 3.07101 2.177712 2.778335 NA Retinopathy NA NA NA

349 NGFR 1.513067 3.996535 2.118628 3.175222 NA NA NA NA Neuropathy

350 NME2 4.864737 6.717417 5.468322 6.290049 NA Retinopathy NA NA NA

351 NOS1 0.36105 2.966727 0.620934 1.702268 NA Retinopathy NA Nephropathy Neuropathy

352 NOS3 1.655766 2.437099 2.008527 2.346727 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 353 NOV 2.057173 3.257919 2.474534 3.082406 NA NA NA Nephropathy NA

354 NOX1 1.014263 2.021089 1.539444 1.956147 NA NA NA Nephropathy NA

355 NOX3 0.791776 2.348755 1.204139 1.811628 NA NA NA Nephropathy NA

356 NOX4 1.410099 3.495255 1.5759 2.711691 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 357 NPHS1 1.60527 2.977732 2.184865 2.851292 NA NA NA Nephropathy NA

358 NPPA 0.957446 2.625901 1.448355 2.351617 Cardiovascular NA NA NA NA diseases 359 NPY 0.534206 2.09889 1.157883 1.766882 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 360 NPY2R 0.231566 1.994984 0.932151 1.754359 Cardiovascular NA NA NA NA diseases 361 NPY5R 1.716139 3.608847 1.998754 2.760329 Cardiovascular NA NA NA NA diseases 362 NQO1 3.810475 5.543232 4.274819 5.074656 Cardiovascular NA Atherosclerosi NA NA diseases s 363 NR1H3 4.140195 5.520312 4.515699 5.137457 NA NA NA Nephropathy NA

364 NR3C2 2.596718 3.887756 2.883129 3.497639 Cardiovascular NA NA NA NA diseases 365 NRF1 1.054715 2.324759 1.363343 2.048539 NA NA NA NA Neuropathy

366 NTF3 1.2599 3.28214 1.476895 2.288278 NA NA NA NA Neuropathy

367 NTS 1.859938 3.208907 2.24503 2.872037 Cardiovascular NA NA NA NA diseases 368 NUCB2 5.041935 6.05772 5.341857 5.795646 Cardiovascular Retinopathy NA NA NA diseases 369 ONECU 1.085749 2.343182 1.296297 1.886772 NA NA NA Nephropathy NA T1 370 OSM 1.118508 3.748178 1.329016 2.590627 NA NA NA Nephropathy NA

371 OXT 2.556724 3.324306 2.773755 3.198355 Cardiovascular NA NA NA NA diseases 372 P2RX2 1.816324 3.202315 2.293374 2.953134 NA NA NA NA Neuropathy

373 P2RX3 1.026036 2.135301 1.214309 1.774278 NA NA NA NA Neuropathy

374 P2RY1 1.809111 3.390957 1.938069 2.771292 NA NA NA NA Neuropathy

375 P2RY2 1.198481 3.391951 1.567287 2.513245 NA NA NA NA Neuropathy

376 PAK6 0.58979 2.308312 1.149893 1.847598 NA NA NA NA Neuropathy

377 PARP1 4.611979 5.402512 4.75124 5.187611 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 378 PC 2.542427 4.456726 3.173434 4.142305 NA NA NA Nephropathy NA

379 PCSK9 1.321192 2.285561 1.522656 2.00083 Cardiovascular NA Atherosclerosi NA NA diseases s 380 PDE5A 0.747949 2.496405 0.935181 1.719502 NA NA NA Nephropathy Neuropathy

381 PDGFB 1.051729 2.154293 1.302766 1.791546 NA NA NA Nephropathy NA

382 PDGFD 4.598284 5.94589 4.835022 5.517858 NA NA Atherosclerosi NA NA s 383 PDGFR 5.335547 7.166986 5.575113 6.434503 NA NA NA Nephropathy NA B 384 PDHX 4.11671 5.268979 4.430959 5.036608 NA Retinopathy NA NA NA

385 PDK1 0.649373 3.340831 1.739706 2.967344 NA NA NA Nephropathy NA

386 PDPK1 2.971899 4.523671 3.405764 4.003132 NA NA NA Nephropathy NA

387 PFKFB 2.516844 3.852654 3.054912 3.698419 NA NA NA Nephropathy NA 2 388 PGF 1.730939 2.993194 2.28226 2.80277 Cardiovascular NA NA NA NA diseases 389 PHACT 2.361702 4.605629 2.638717 3.616029 Cardiovascular NA NA NA NA R1 diseases 390 PIGF 3.855614 4.273054 3.973416 4.171018 NA Retinopathy NA NA NA

391 PIK3CA 3.122689 4.317503 3.333011 3.869343 NA NA NA Nephropathy NA

392 PIP 0.992955 2.326973 1.237345 1.86803 NA NA NA Nephropathy NA

393 PLA2G2 4.446175 6.96407 5.173605 6.534585 NA NA Atherosclerosi NA NA A s 394 PLEKH 2.249309 3.322392 2.523782 2.982059 NA NA NA Nephropathy NA H2 395 PLN 2.669576 3.67406 3.000316 3.449809 Cardiovascular NA NA NA NA diseases 396 PLTP 3.700339 6.767445 4.590906 6.225885 NA NA Atherosclerosi NA NA s 397 PLXDC 2.044546 3.198724 2.315622 2.822859 NA Retinopathy NA NA NA 1 398 PMP22 5.445318 6.310444 5.548904 6.005869 NA NA NA NA Neuropathy

399 POLR2 2.504444 3.532267 2.742519 3.309754 NA Retinopathy NA NA NA D 400 POMC 2.560565 4.093444 2.819487 3.481501 Cardiovascular NA NA NA Neuropathy diseases 401 PON1 0.781026 2.398806 1.056669 1.706199 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 402 PON2 3.8252 5.228905 4.295912 4.986646 NA NA Atherosclerosi Nephropathy NA s 403 PON3 2.030208 3.280114 2.269846 2.87135 Cardiovascular NA Atherosclerosi NA NA diseases s 404 POSTN 4.312365 6.494814 4.609836 5.772017 NA Retinopathy NA Nephropathy NA

405 PPARA 1.975109 2.554839 2.135954 2.484326 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 406 PPARG 3.556738 5.581661 3.92271 5.021461 NA Retinopathy Atherosclerosi Nephropathy NA s 407 PPARG 1.91707 3.538188 2.531487 3.292541 Cardiovascular Retinopathy NA Nephropathy Neuropathy C1A diseases 408 PPY 2.729779 3.914492 3.002884 3.621446 NA NA NA NA Neuropathy

409 PRCP 4.791638 5.493935 4.913215 5.291826 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 410 PRDX1 6.416062 7.086351 6.539162 6.93199 Cardiovascular NA NA NA NA diseases 411 PRDX2 3.916127 5.283427 3.996529 4.662826 Cardiovascular NA NA NA NA diseases 412 PRDX4 4.811039 5.778365 4.883241 5.405351 Cardiovascular NA NA NA NA diseases 413 PRDX6 6.267863 7.769964 6.918016 7.620323 Cardiovascular NA NA NA NA diseases 414 PRKAA 2.694819 3.316666 2.711279 3.035801 NA NA NA Nephropathy NA 1 415 PRKCE 0.908851 2.456404 1.198184 1.99274 NA NA NA Nephropathy NA

416 PRKG1 0.956794 3.037901 1.828954 2.766979 NA NA NA NA Neuropathy

417 PROC 0.896343 1.693445 1.166173 1.608378 NA NA NA Nephropathy NA

418 PROM1 0.665885 2.668768 0.980822 2.025809 NA NA NA NA Neuropathy

419 PSIP1 4.644136 5.615229 4.970359 5.402088 NA Retinopathy NA NA NA

420 PSMA6 5.136858 6.394078 5.444825 5.951509 Cardiovascular NA NA Nephropathy NA diseases 421 PSMD9 2.076168 3.597522 2.546556 3.314478 NA Retinopathy NA Nephropathy Neuropathy

422 PTEN 5.502679 7.002298 6.029031 6.636533 NA NA NA Nephropathy Neuropathy

423 PTGDS 4.891666 6.36981 5.094736 5.80444 NA NA Atherosclerosi Nephropathy NA s 424 PTGER 0.556777 2.41863 1.115942 2.058911 NA NA NA Nephropathy NA 1 425 PTGER 2.621709 4.650542 3.027898 4.092791 NA NA NA Nephropathy NA 4 426 PTGES 3.355127 4.384065 3.617446 4.112145 NA NA NA Nephropathy NA

427 PTGS2 2.521948 7.673075 3.530082 5.764726 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 428 PTH 0.950789 2.496111 1.214322 1.91185 Cardiovascular NA NA Nephropathy NA diseases 429 PTPN1 2.573194 4.150866 2.730647 3.44522 Cardiovascular NA NA Nephropathy NA diseases 430 PTX3 2.075085 5.62023 2.406791 4.158911 NA Retinopathy Atherosclerosi Nephropathy NA s 431 RAF1 4.539542 5.038685 4.69009 4.938623 NA Retinopathy NA Nephropathy NA

432 RARRES 5.710609 7.566696 6.302733 7.245211 Cardiovascular NA NA NA NA 2 diseases 433 RBP1 3.561633 5.591999 4.213255 5.121878 NA Retinopathy NA NA NA

434 RBP4 3.861648 7.243595 4.650426 6.420443 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 435 REG1A 0.896757 2.709311 1.133785 1.894631 NA NA NA Nephropathy NA

436 RELA 1.19163 3.211456 1.81807 2.825326 NA Retinopathy NA Nephropathy NA

437 REN 0.847921 2.455582 1.297022 1.962665 Cardiovascular NA Atherosclerosi NA NA diseases s 438 RETN 0.222208 2.861953 0.9617 2.188704 Cardiovascular NA Atherosclerosi NA NA diseases s 439 RGN 2.785951 3.963321 3.273157 3.757555 NA NA NA Nephropathy NA

440 RHO 1.284476 2.304885 1.598102 2.090905 NA Retinopathy NA NA NA

441 RHOA 6.311852 7.429363 6.606522 7.119206 NA NA NA NA Neuropathy

442 RHOD 1.941012 3.395451 2.462285 3.076785 NA NA NA Nephropathy NA

443 ROCK1 3.471907 5.202679 3.747343 4.615932 NA NA NA Nephropathy NA

444 ROCK2 3.588246 4.800323 3.847189 4.494274 NA NA Atherosclerosi NA NA s 445 RPS12 6.138042 7.61498 6.602614 7.33054 NA NA NA Nephropathy NA

446 RPS6 7.89132 8.845726 8.12152 8.579859 NA NA NA Nephropathy NA

447 RPS6KA 1.052262 2.149698 1.2555 1.810868 NA NA NA NA Neuropathy 6 448 RREB1 1.360956 3.070877 1.589485 2.350685 NA NA NA Nephropathy NA

449 RTN1 3.43392 4.813568 3.880375 4.557718 NA NA NA Nephropathy NA

450 S100A1 1.35933 4.8971 2.558981 4.306087 Cardiovascular Retinopathy NA NA NA 2 diseases 451 SAA1 2.567482 7.468512 5.152242 7.178905 NA Retinopathy NA Nephropathy NA

452 SARDH 0.5491 2.422419 1.06884 1.887106 NA Retinopathy NA NA NA

453 SCARB1 3.240986 3.998812 3.402204 3.77869 NA NA Atherosclerosi NA NA s 454 SELE 1.486133 6.874851 2.055664 4.390016 NA NA NA Nephropathy NA

455 SEMA3 3.362877 4.638822 3.840906 4.441261 NA NA NA Nephropathy NA A 456 SERPIN 0.630046 2.220491 0.948118 1.86031 NA NA NA Nephropathy NA B7 457 SERPIN 1.280323 4.118047 1.97832 3.372649 NA NA NA Nephropathy NA E1 458 SERPIN 7.121009 8.774594 7.323359 8.004188 NA Retinopathy NA Nephropathy Neuropathy F1 459 SERPIN 1.743665 2.788003 1.941205 2.576194 NA NA NA Nephropathy NA F2 460 SFI1 2.852525 3.838321 3.085798 3.604753 NA NA NA Nephropathy NA

461 SGK2 3.06453 4.190702 3.276766 3.8943 NA NA NA Nephropathy NA

462 SHBG 1.273351 2.806139 1.340032 2.068116 Cardiovascular NA NA NA NA diseases

463 SIRT1 2.61354 4.186151 2.994967 3.631801 Cardiovascular Retinopathy Atherosclerosi NA NA diseases s 464 SIRT6 3.233724 3.807464 3.332698 3.653901 NA NA NA Nephropathy NA

465 SLC12A 1.39378 2.654154 1.571053 2.296492 NA NA NA Nephropathy NA 3 466 SLC22A 1.301005 3.695324 2.028253 3.028228 NA NA NA Nephropathy NA 6 467 SLC2A1 2.06713 4.525137 2.205507 3.422062 Cardiovascular NA NA Nephropathy NA diseases 468 SLC2A2 1.56972 2.833576 1.849768 2.414297 NA NA NA Nephropathy NA

469 SLC2A3 4.500309 7.080932 4.795395 6.31929 NA NA NA NA Neuropathy

470 SLC2A4 1.190092 3.348775 1.65103 2.612515 Cardiovascular NA NA Nephropathy Neuropathy diseases 471 SLC30A 1.076691 2.474913 1.258401 1.879814 NA NA NA NA Neuropathy 10 472 SLC30A 1.223739 3.013767 1.591029 2.264537 NA NA NA Nephropathy NA 8 473 SLC5A2 0.862386 2.198041 1.090703 1.719514 Cardiovascular NA NA NA NA diseases 474 SLC9A1 2.155462 3.257914 2.352946 2.90925 NA NA NA Nephropathy NA

475 SLMAP 3.924891 5.095021 4.329121 4.886657 NA Retinopathy NA NA NA

476 SMAD1 3.885663 4.447554 4.044632 4.351678 NA NA NA Nephropathy NA

477 SMAD7 3.322006 4.564673 3.547609 4.113432 NA NA NA Nephropathy NA

478 SMG1 1.877916 3.871916 2.296322 3.300731 NA Retinopathy NA NA NA

479 SMPD1 3.040421 3.772887 3.263516 3.607888 NA Retinopathy NA NA NA

480 SOCS1 2.383034 3.726808 2.90832 3.503391 NA NA NA Nephropathy NA

481 SOCS2 3.117998 4.287242 3.365912 4.006944 NA NA NA Nephropathy NA

482 SOCS3 2.630568 4.984649 3.001527 4.272062 NA Retinopathy NA Nephropathy NA

483 SOD1 7.061703 8.29004 7.414143 8.113511 NA Retinopathy NA Nephropathy NA

484 SOD2 3.928181 6.135403 4.25611 5.364607 NA Retinopathy NA NA Neuropathy

485 SOST 0.833326 2.438123 1.123461 1.809056 Cardiovascular NA Atherosclerosi NA NA diseases s 486 SOX9 2.317921 4.498003 2.531983 3.503299 NA NA NA Nephropathy NA

487 SPARC 6.187798 8.521927 6.986515 7.820614 NA Retinopathy NA Nephropathy NA

488 SPON2 2.989514 4.427322 3.366945 4.05711 NA NA NA Nephropathy NA

489 SPP1 2.35601 5.286459 3.029618 4.552355 Cardiovascular Retinopathy NA Nephropathy NA diseases 490 SRC 1.294212 1.982387 1.438644 1.832023 NA NA NA Nephropathy NA

491 SREBF1 2.695637 4.071206 3.157259 3.755609 NA NA NA Nephropathy Neuropathy

492 SST 0.894017 2.274594 1.156761 1.856366 NA Retinopathy NA Nephropathy NA

493 STAT1 3.9671 6.371151 4.545063 5.566352 NA NA NA Nephropathy NA

494 STAT3 4.490913 5.980205 4.670464 5.324923 NA Retinopathy NA Nephropathy NA

495 STAT5A 3.790032 5.185627 4.374386 5.012069 NA NA NA Nephropathy NA

496 STK11 1.038209 4.114925 2.452342 3.846286 NA NA NA Nephropathy NA

497 SUCNR 3.07121 4.009074 3.233592 3.655508 NA NA NA Nephropathy NA 1 498 SYVN1 3.921061 4.684006 4.059548 4.464548 NA Retinopathy NA NA NA

499 TACR1 1.006053 2.240121 1.28111 1.907211 Cardiovascular NA NA NA NA diseases 500 TCF7L2 2.393598 3.621809 2.807672 3.43555 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 501 TF 3.711415 5.828249 4.176326 5.294023 NA NA NA Nephropathy NA

502 TFAM 3.142536 4.780069 3.481354 4.318363 NA NA NA NA Neuropathy

503 TGFBR 1.262934 2.134493 1.345018 1.811042 NA NA NA Nephropathy NA 1 504 TH 1.405029 3.192546 1.644229 2.615699 NA Retinopathy NA NA Neuropathy

505 THBD 3.194179 5.484269 3.337515 4.348119 NA NA NA Nephropathy NA

506 THBS1 4.967583 6.837282 5.278957 6.439346 NA Retinopathy NA Nephropathy NA

507 THBS2 4.036549 6.110052 4.389493 5.614144 NA NA NA Nephropathy NA

508 TIMM44 2.872666 3.887752 3.114595 3.523729 NA NA NA Nephropathy NA

509 TIMP1 6.845156 8.336394 7.381393 8.081288 NA Retinopathy NA NA NA

510 TIMP2 6.041851 7.78795 6.195508 7.045781 NA NA NA Nephropathy NA

511 TIMP3 6.784526 8.316638 7.09546 7.85918 NA Retinopathy Atherosclerosi Nephropathy NA s 512 TKT 5.001376 6.118659 5.28193 5.978982 NA NA NA Nephropathy Neuropathy

513 TLR2 3.246639 4.739288 3.533536 4.385546 NA NA NA Nephropathy NA

514 TLR4 2.815689 5.105432 3.290148 4.343544 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 515 TM6SF2 0.899609 3.430182 1.06249 2.18455 Cardiovascular NA NA NA NA diseases 516 TNF 1.949828 3.780541 2.610432 3.498461 NA Retinopathy NA Nephropathy Neuropathy

517 TNFAIP 3.215515 4.945553 3.776996 4.541897 NA NA NA Nephropathy NA 8 518 TNFRSF 1.792797 3.604837 2.370106 3.361061 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy 11B diseases s 519 TNFRSF 2.367098 5.633812 3.067682 4.693349 NA NA NA NA Neuropathy 1B 520 TPM1 4.386671 5.271652 4.5701 5.017626 Cardiovascular NA NA NA NA diseases 521 TRAF6 2.712912 3.618832 2.791527 3.260172 NA NA NA NA Neuropathy

522 TRH 2.618843 4.438561 2.749398 3.527608 NA NA NA NA Neuropathy

523 TRIB3 2.223586 3.39329 2.49531 3.064284 Cardiovascular NA NA Nephropathy NA diseases 524 TRPA1 0.624595 1.869211 1.035597 1.647544 NA NA NA NA Neuropathy

525 TRPC1 3.366958 4.21709 3.561986 3.961676 NA NA NA Nephropathy NA

526 TRPC6 1.518206 3.098505 1.979965 2.703607 NA NA Atherosclerosi Nephropathy NA s 527 TRPV1 1.679485 2.767252 2.077208 2.641189 NA NA NA NA Neuropathy

528 TRPV3 0.794306 2.150613 1.142069 1.868074 NA NA NA NA Neuropathy

529 TRPV4 0.872084 2.59136 1.385171 2.167952 NA NA NA Nephropathy NA

530 TSC1 2.195033 3.580026 2.699754 3.341809 NA NA NA Nephropathy NA

531 TSC2 3.344092 3.863383 3.503286 3.773218 NA NA NA Nephropathy NA

532 TXNIP 7.869946 9.28552 8.433485 9.17883 NA Retinopathy Atherosclerosi Nephropathy NA s 533 UCP1 0.974641 2.753668 1.246586 2.111864 NA Retinopathy NA NA NA

534 UCP2 4.595236 6.46697 5.082709 6.017714 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 535 UHRF1 0.7862 2.94574 1.753857 2.71012 NA NA NA Nephropathy NA

536 UMOD 1.755791 4.007161 2.432277 3.308689 NA NA NA Nephropathy NA

537 UNC13 3.011467 4.079147 3.366888 3.839783 NA NA NA Nephropathy NA B 538 UNC5B 1.240159 2.447839 1.507461 2.141758 NA NA NA Nephropathy NA

539 USF2 2.890645 4.375814 3.358682 4.060644 NA NA NA Nephropathy NA

540 UTRN 2.498468 4.581434 3.373319 4.25368 NA NA NA Nephropathy NA

541 UTS2 0.89193 2.579585 1.228727 2.117874 NA Retinopathy Atherosclerosi NA NA s 542 UTS2R 1.935991 2.787483 2.138626 2.513392 NA NA NA Nephropathy NA

543 VCAM1 4.60202 6.495137 4.663768 5.598939 Cardiovascular NA Atherosclerosi NA NA diseases s 544 VDAC1 6.104946 6.827541 6.330135 6.688676 NA NA NA Nephropathy NA

545 VDAC2 5.388741 6.297105 5.709084 6.047832 NA NA NA Nephropathy NA

546 VDR 1.731607 3.065485 1.911372 2.614101 Cardiovascular Retinopathy NA Nephropathy NA diseases 547 VEGFC 3.798912 4.389051 4.027573 4.327372 NA Retinopathy NA NA NA

548 VIP 1.402785 2.68542 1.758687 2.420059 NA NA NA NA Neuropathy

549 VWF 4.334121 6.437464 4.823344 5.845347 Cardiovascular NA NA Nephropathy Neuropathy diseases 550 WFS1 4.316895 5.421203 4.539547 5.177613 NA NA NA Nephropathy NA

551 WT1 3.38531 5.891306 4.452817 5.691578 NA NA NA Nephropathy NA

552 XBP1 4.501638 6.487377 4.774958 5.776122 NA NA NA Nephropathy NA

553 XRCC1 3.289588 4.065509 3.511099 3.927249 Cardiovascular Retinopathy NA NA NA diseases 554 ZNF236 1.707549 3.215084 1.934699 2.584154 NA NA NA Nephropathy NA

555 ZNRF1 1.43699 2.73435 1.591022 2.176634 NA Retinopathy NA NA NA

Table A.2: table for blood tissue

Genes Actual Actual 99% CI 99% CI complication1 complicatio complication3 complicatio complication5 Min Max Min Max n2 n4 1 ABCA1 6.811903 9.908257 7.627332 8.242212 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 2 ABCG1 6.103429 8.416198 6.872404 7.382094 Cardiovascular NA Atherosclerosis NA NA diseases 3 ABO 3.448075 6.464957 4.183072 4.811483 Cardiovascular NA NA NA NA diseases 4 ACACB 2.933821 6.554587 4.137681 5.004324 NA NA NA Nephropathy NA

5 ACAT1 7.599527 10.12139 9.217401 9.649286 NA NA Atherosclerosis NA NA

6 ACE 3.184307 7.379303 4.680364 5.633252 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 7 ACSL1 8.043271 11.46708 9.216446 9.924843 NA NA Atherosclerosis NA NA

8 ACVRL1 3.940628 7.411107 5.360117 6.210857 NA NA NA Nephropathy NA

9 ADAM10 9.615501 11.86735 10.95357 11.33653 NA NA NA Nephropathy NA

10 ADAM17 7.633402 9.738548 8.344835 8.789316 NA NA Atherosclerosis Nephropathy NA

11 ADCYAP 3.948227 7.658118 5.599004 6.626182 NA Retinopathy NA Nephropathy NA 1 12 ADH1B 2.080215 7.23482 4.621708 5.83866 NA NA NA Nephropathy Neuropathy

13 ADIPOQ 3.774767 6.557637 5.062091 5.71846 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 14 ADK 9.349212 10.6714 9.727466 10.08612 NA Retinopathy NA NA NA

15 ADM 7.140234 10.82296 8.431991 9.314892 NA Retinopathy NA Nephropathy Neuropathy

16 AGER 6.646915 8.694361 7.489234 7.925016 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 17 AGT 4.314472 7.125983 5.913404 6.533759 NA NA NA Nephropathy Neuropathy

18 AGTR1 4.779254 7.39652 5.791121 6.460384 NA NA NA Nephropathy NA

19 AHSA1 8.809762 10.63238 9.816457 10.17632 Cardiovascular Retinopathy NA Nephropathy NA diseases 20 AHSG 2.444725 6.682514 4.215279 5.394622 Cardiovascular Retinopathy NA Nephropathy NA diseases 21 AKR1B1 9.77662 10.98249 10.40787 10.68296 NA Retinopathy NA Nephropathy Neuropathy

22 AKR1B10 2.108108 7.50432 4.726759 6.005272 NA NA NA Nephropathy NA

23 AKT1 8.105902 10.00538 9.184516 9.546202 Cardiovascular Retinopathy NA Nephropathy NA diseases 24 ALB 2.540124 6.902917 4.75083 5.833015 NA NA Atherosclerosis Nephropathy Neuropathy

25 ALDH1A 6.486178 9.999563 8.319079 9.159846 NA NA NA Nephropathy NA 1 26 ALDH2 10.52085 11.9718 10.96296 11.33794 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 27 ALOX5A 10.78314 12.33499 11.44487 11.8308 NA NA Atherosclerosis Nephropathy NA P 28 ALPL 3.281581 7.636363 5.363584 6.208908 NA NA NA Nephropathy NA

29 AMBP 2.421478 4.6611 3.310235 3.859681 NA NA NA Nephropathy NA

30 ANG 4.199747 8.68829 6.457677 7.319598 NA NA NA Nephropathy NA

31 ANGPT2 2.607994 7.180537 3.782741 4.916931 NA Retinopathy NA NA NA

32 ANGPTL 4.810136 8.35661 7.115933 7.764133 NA NA Atherosclerosis Nephropathy NA 2 33 AOC2 3.890272 7.475734 5.559373 6.338589 NA NA NA Nephropathy NA

34 AOC3 3.017087 6.820578 4.784072 5.686732 NA Retinopathy NA NA NA

35 APC 6.860454 9.120068 7.782701 8.262218 NA NA NA Nephropathy NA

36 API5 7.767314 9.618914 8.646113 9.029884 NA Retinopathy NA NA NA

37 APLNR 3.177241 6.128117 4.274461 5.052093 NA NA NA Nephropathy NA

38 APOA1 3.271157 7.973414 4.965448 6.171622 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 39 APOB 3.11042 7.168885 5.082898 6.022889 Cardiovascular Retinopathy NA NA Neuropathy diseases 40 APOC1 3.506112 6.454495 4.403628 5.037096 NA NA NA Nephropathy NA

41 APOC3 2.987954 5.731141 3.789726 4.483223 Cardiovascular NA NA Nephropathy NA diseases 42 APOE 2.575656 7.575334 4.618059 5.795482 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 43 APOH 2.492005 7.169823 4.366965 5.621869 Cardiovascular NA NA NA NA diseases 44 APOL1 4.156624 8.467341 6.813193 7.570667 Cardiovascular NA NA Nephropathy NA diseases 45 APOM 5.75967 8.702707 7.062684 7.618028 NA NA Atherosclerosis NA NA

46 AQP1 2.578059 7.82436 5.655701 6.632154 NA Retinopathy NA NA NA

47 AQP4 1.141727 6.08239 2.038248 3.378808 NA Retinopathy NA NA NA

48 AQP5 3.151985 6.773747 4.410532 5.141344 NA NA NA Nephropathy NA

49 AR 4.242634 7.732059 5.818079 6.662748 NA NA NA Nephropathy NA

50 ASPA 1.963901 6.882151 3.539608 4.781629 NA NA NA NA Neuropathy

51 ATF4 11.384 13.19149 12.17115 12.61711 NA Retinopathy NA Nephropathy NA

52 ATM 9.195041 11.80395 10.36087 10.99522 Cardiovascular NA NA NA NA diseases 53 ATP2A2 9.510081 11.46182 10.0589 10.38251 NA NA NA NA Neuropathy

54 B2M 14.39099 15.63531 14.71307 15.01429 NA NA Atherosclerosis Nephropathy NA

55 BAAT 2.522092 5.961123 3.208412 3.882179 NA NA Atherosclerosis NA NA

56 BAMBI 4.719643 7.78072 6.486631 7.110289 NA NA NA Nephropathy NA

57 BASP1 10.00431 12.74699 10.61582 11.17409 NA NA NA Nephropathy NA

58 BCL2 2.973502 7.676103 5.204242 6.531535 NA NA NA Nephropathy NA

59 BDKRB1 3.694107 7.551366 5.140291 6.219789 NA NA NA NA Neuropathy

60 BDKRB2 2.959002 6.402323 4.487933 5.194152 NA NA NA NA Neuropathy

61 BDNF 2.320886 6.540645 3.639959 4.649929 NA Retinopathy NA NA Neuropathy

62 BMP2 1.687833 6.783857 3.662192 4.93407 NA NA Atherosclerosis NA NA

63 BMP4 2.948225 5.483544 3.473715 3.968188 NA NA NA Nephropathy NA

64 BNIP3 7.105707 8.842359 7.829867 8.251982 Cardiovascular NA NA NA NA diseases 65 C5 4.802946 7.756779 6.086852 6.705503 NA Retinopathy NA Nephropathy NA

66 CACNA1 3.044626 6.076969 3.874213 4.52241 NA NA NA NA Neuropathy H 67 CAT 10.22274 13.01679 11.95579 12.44616 NA Retinopathy NA Nephropathy NA

68 CAV1 3.396469 7.368422 5.324522 6.178523 NA NA NA Nephropathy Neuropathy

69 CCK 3.131241 6.963649 4.081981 5.068554 NA NA NA Nephropathy Neuropathy

70 CCKAR 3.454937 7.082263 4.692652 5.549698 NA NA NA Nephropathy NA

71 CCL2 2.279993 6.957121 4.170952 5.219781 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

72 CCL20 1.609506 5.205337 2.901605 3.719991 NA NA NA Nephropathy NA

73 CCL5 10.24461 12.68362 11.27581 11.86885 NA NA NA Nephropathy NA

74 CCR1 9.076149 11.58894 9.847225 10.4258 NA NA NA Nephropathy NA

75 CCR2 8.073078 12.59405 9.733003 10.56567 NA NA Atherosclerosis Nephropathy NA

76 CCR5 6.618094 10.15447 8.240213 8.954331 NA NA Atherosclerosis Nephropathy NA

77 CD160 7.700751 11.1116 8.678428 9.466554 NA Retinopathy NA NA NA

78 CD163 8.710817 11.17376 10.01508 10.57378 NA Retinopathy Atherosclerosis NA Neuropathy

79 CD247 10.59302 12.73845 11.55338 11.9854 Cardiovascular NA NA NA NA diseases 80 CD2AP 7.514365 9.252941 8.033627 8.492479 NA NA NA Nephropathy NA

81 CD34 5.447934 7.745597 6.734139 7.233793 NA NA NA NA Neuropathy

82 CD36 8.14829 12.14985 9.964393 10.97735 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 83 CD38 6.89122 10.35985 8.240052 8.924958 NA NA NA Nephropathy NA

84 CD4 9.191747 11.81986 10.25671 10.77417 Cardiovascular NA Atherosclerosis NA NA diseases 85 CD40 5.051456 9.269157 7.517667 8.216815 Cardiovascular NA Atherosclerosis NA NA diseases 86 CD40LG 6.332256 8.866841 7.273657 7.887512 Cardiovascular NA NA Nephropathy NA diseases 87 CD47 10.73599 11.93324 11.07026 11.3423 NA NA NA Nephropathy NA

88 CD59 8.63374 10.79712 9.364907 9.827533 NA Retinopathy NA NA NA

89 CD63 11.42529 12.55744 11.8577 12.14257 NA NA NA Nephropathy NA

90 CD68 5.943256 8.629876 7.19104 7.762179 NA NA NA Nephropathy NA

91 CD69 7.922057 11.70242 9.855963 10.60943 NA NA NA Nephropathy NA

92 CD74 12.92292 14.48526 13.59092 13.98664 NA NA NA Nephropathy NA

93 CD80 6.225676 7.928059 6.818019 7.224251 NA NA NA Nephropathy NA

94 CD9 6.843338 10.32627 8.255069 8.993942 Cardiovascular NA NA NA NA diseases 95 CDC123 9.796881 10.82544 10.07242 10.33759 Cardiovascular NA NA NA NA diseases 96 CDH1 1.81789 7.290637 3.806883 5.391097 NA NA NA Nephropathy NA

97 CDH2 2.364132 7.067871 3.950742 4.935467 NA NA NA Nephropathy NA

98 CDK7 7.570652 9.485177 8.420132 8.78748 NA NA NA Nephropathy NA

99 CDKN1A 7.021865 9.812466 8.493906 9.055489 NA NA NA Nephropathy NA

100 CDKN2A 2.130008 6.917323 4.859428 5.967917 Cardiovascular NA NA NA NA diseases 101 CETP 2.271086 5.293636 3.448804 4.269686 Cardiovascular NA Atherosclerosis NA NA diseases 102 CHI3L1 2.996613 9.28337 4.72993 6.571192 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 103 CHIT1 2.826112 5.776306 4.069799 4.752103 NA NA NA Nephropathy NA

104 CHN2 6.036137 8.490276 6.966033 7.559744 NA Retinopathy NA Nephropathy NA

105 CITED2 8.179441 9.844813 9.023979 9.456323 NA NA Atherosclerosis NA NA

106 CLCN5 4.597628 6.898932 5.712524 6.240917 NA NA NA Nephropathy NA

107 CLEC11 4.64008 8.258045 5.926673 6.866747 NA NA NA Nephropathy NA A 108 CLOCK 7.746762 9.705738 8.81298 9.277982 Cardiovascular NA NA NA NA diseases 109 CMA1 2.390415 6.872056 4.609721 5.679922 NA NA NA Nephropathy NA

110 CMC4 8.330776 10.04677 8.861995 9.207073 NA NA NA Nephropathy NA

111 CNR1 2.706879 6.531581 4.012695 4.801992 NA Retinopathy NA Nephropathy Neuropathy

112 CNR2 6.315913 8.426848 7.196142 7.705342 NA NA NA Nephropathy Neuropathy

113 CNTF 3.683543 6.958075 5.421458 6.124621 NA NA NA NA Neuropathy

114 COG2 9.084279 9.910541 9.385362 9.578522 NA NA Atherosclerosis NA NA

115 COL8A1 1.469694 7.067465 3.71712 5.107897 NA NA NA Nephropathy NA

116 COMT 8.342793 10.45284 9.463591 9.890114 Cardiovascular NA NA NA NA diseases 117 CPVL 9.747231 11.99621 10.74383 11.27274 NA NA NA Nephropathy NA

118 CRH 2.558668 7.348349 4.229839 5.13166 NA NA NA NA Neuropathy

119 CRK 8.130232 9.516436 8.595824 8.957313 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 120 CRP 2.15807 6.539718 3.321772 4.208552 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 121 CST3 10.43967 12.90138 11.39852 11.97272 Cardiovascular NA NA NA NA diseases 122 CTGF 1.042075 6.093062 3.023377 4.124403 NA Retinopathy NA Nephropathy NA

123 CTSH 10.51691 12.48327 11.24883 11.70503 NA Retinopathy NA NA NA

124 CTSS 7.295855 11.12017 9.267035 10.16342 Cardiovascular NA NA NA NA diseases 125 CUBN 4.79793 8.268645 6.070712 6.846005 NA NA NA Nephropathy NA

126 CX3CL1 3.501682 7.78681 4.795148 5.639098 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 127 CX3CR1 9.092139 13.6281 11.95419 12.75698 NA NA NA Nephropathy NA

128 CXCL10 6.483824 9.260604 7.229434 7.921262 NA NA NA Nephropathy Neuropathy

129 CXCL11 0.529547 6.442459 2.853896 4.410011 NA NA NA Nephropathy NA

130 CXCL12 5.757693 8.19156 6.768182 7.40409 NA NA NA Nephropathy NA

131 CXCL5 1.276131 6.145049 3.358191 4.668782 NA NA Atherosclerosis Nephropathy NA

132 CXCL8 6.08419 12.10965 8.428268 10.04386 NA NA NA Nephropathy NA

133 CXCL9 3.799092 8.020145 6.183066 6.942335 NA NA NA Nephropathy NA

134 CYBA 11.03593 12.92256 11.96535 12.35569 NA NA Atherosclerosis Nephropathy NA

135 CYBB 9.097422 11.65042 10.23409 10.86577 NA Retinopathy NA NA NA

136 CYP1A1 3.119113 7.474981 5.083194 6.161925 Cardiovascular NA Atherosclerosis NA NA diseases 137 CYP24A1 1.839004 7.358583 3.81706 5.145401 NA NA NA Nephropathy NA

138 CYP2C19 3.624554 8.725641 5.211155 6.269708 NA Retinopathy NA NA NA

139 CYP2J2 2.927361 6.542058 4.077129 5.132964 Cardiovascular NA NA Nephropathy NA diseases 140 CYP7A1 -1.26474 5.671377 1.734185 3.466053 Cardiovascular NA NA NA NA diseases 141 CYR61 2.726109 7.259115 4.443723 5.514393 NA Retinopathy NA NA NA

142 DDAH1 1.950839 7.321521 3.99465 5.387357 NA Retinopathy NA Nephropathy NA

143 DDIT3 7.699291 9.736912 8.504171 8.945115 Cardiovascular NA NA Nephropathy Neuropathy diseases 144 DEFA1 8.534184 14.90193 10.80715 12.5169 NA NA NA Nephropathy NA

145 DES 3.096407 7.529917 4.845935 6.003361 NA NA NA Nephropathy NA

146 DHCR7 4.100001 8.657035 6.782821 7.687465 NA NA Atherosclerosis NA NA

147 DKK1 2.427021 8.117886 4.849034 6.228901 Cardiovascular Retinopathy NA Nephropathy NA diseases 148 DNMT1 9.196558 10.98868 10.00722 10.36374 NA NA NA Nephropathy NA

149 DPP4 3.708616 9.04283 6.71959 7.956068 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 150 EDNRA 0.291607 6.114358 2.607295 4.205217 NA NA NA Nephropathy NA

151 EGF 4.475208 6.986079 5.666659 6.387318 NA NA NA Nephropathy NA

152 EGFR 2.500706 6.982376 4.064045 5.250449 Cardiovascular NA NA Nephropathy NA diseases 153 EIF4EBP 8.185743 9.795548 8.868722 9.240563 NA NA NA Nephropathy NA 1 154 ELMO1 7.987143 9.370474 8.540621 8.89711 NA NA NA Nephropathy NA

155 ELN 3.697748 6.953714 4.377237 4.987132 NA NA Atherosclerosis NA NA

156 ENG 4.257111 8.195083 5.885408 6.871846 Cardiovascular Retinopathy NA NA Neuropathy diseases 157 ENPP1 2.315095 6.074807 3.375196 4.34711 NA NA NA Nephropathy NA

158 ENPP2 5.957123 7.946876 6.724049 7.169969 NA NA NA NA Neuropathy

159 ENTPD1 8.020773 9.893256 8.765151 9.258233 NA NA Atherosclerosis Nephropathy NA

160 EPO 1.996534 5.710652 3.184584 4.15612 NA Retinopathy NA Nephropathy Neuropathy

161 EPOR 3.316604 7.851478 5.47158 6.427059 NA NA NA Nephropathy NA

162 ERBB2 2.991405 6.700365 4.355365 5.372876 Cardiovascular NA NA NA Neuropathy diseases 163 ERBB3 4.138981 6.813504 5.326443 6.114981 NA Retinopathy NA NA NA

164 ERBB4 2.586036 7.121649 4.823123 5.699342 NA NA NA Nephropathy NA

165 ERCC1 7.483839 9.326295 8.66588 8.971206 NA Retinopathy NA Nephropathy NA

166 ERCC4 3.696437 7.229373 5.520101 6.473362 NA Retinopathy NA Nephropathy NA

167 ESM1 0.779729 6.719819 4.43817 5.72296 NA NA NA NA Neuropathy

168 ESR1 3.460865 7.338866 5.679305 6.479935 NA NA NA Nephropathy NA

169 EXOSC7 8.395243 9.842677 9.14478 9.436274 NA NA NA Nephropathy NA

170 EZR 8.017888 10.90945 9.332953 10.04362 NA NA NA Nephropathy NA

171 F11 3.671453 7.49076 5.179154 6.13571 NA NA NA Nephropathy NA

172 F2R 4.988856 8.062156 6.433518 7.221347 NA NA NA Nephropathy NA

173 F8 6.444416 8.443744 7.128671 7.592176 NA NA NA NA Neuropathy

174 FABP1 1.481183 4.894488 2.471591 3.283724 Cardiovascular NA NA Nephropathy NA diseases 175 FABP2 3.0566 7.057578 4.845207 5.94294 NA NA NA Nephropathy NA

176 FABP4 1.855656 6.596633 3.938591 4.956111 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 177 FABP5 6.966096 9.692002 7.809284 8.366246 Cardiovascular NA Atherosclerosis NA NA diseases 178 FADS1 6.234666 8.601269 7.389934 7.931236 Cardiovascular NA NA NA NA diseases 179 FADS2 3.458038 8.209532 5.602651 6.661601 Cardiovascular NA NA NA NA diseases 180 FASN 7.125934 9.017411 7.753491 8.165707 NA NA NA Nephropathy NA

181 FGFR1 4.266297 7.855355 6.057507 6.786714 NA NA Atherosclerosis NA NA

182 FKBP2 7.501639 9.690527 8.670777 9.104672 NA NA Atherosclerosis NA NA

183 FKBP4 4.961504 8.368227 7.393271 7.940354 Cardiovascular NA NA NA NA diseases 184 FKBP8 7.107744 9.153029 7.738972 8.248841 Cardiovascular NA NA NA NA diseases 185 FMO3 1.286548 5.665471 2.697619 3.828743 NA NA Atherosclerosis NA NA

186 FMOD 5.255841 8.894376 6.767575 7.47249 NA NA Atherosclerosis NA NA

187 FOLH1 1.753425 7.062612 3.369931 4.552895 NA NA NA NA Neuropathy

188 FOS 8.204558 12.99802 10.74474 11.72588 NA NA NA Nephropathy NA

189 FOXA2 2.458715 4.976732 3.504174 4.151548 NA NA Atherosclerosis NA NA

190 FOXO1 7.899771 10.03778 8.506532 9.081008 NA NA Atherosclerosis NA NA

191 FOXO4 4.75279 7.948551 6.315998 7.176202 NA NA NA Nephropathy NA

192 FPR1 6.02057 8.865348 6.949321 7.601547 NA NA Atherosclerosis NA NA

193 FTO 8.852177 10.69007 9.451155 9.853212 Cardiovascular NA NA Nephropathy NA diseases 194 G6PD 8.005144 9.847706 8.804699 9.238543 Cardiovascular NA NA Nephropathy Neuropathy diseases 195 GAP43 1.274925 6.513621 3.452842 4.848257 NA NA NA NA Neuropathy

196 GAPDH 13.46073 15.35261 14.25472 14.66047 NA Retinopathy NA NA Neuropathy

197 GAS1 1.983757 5.636119 3.00775 3.678998 NA NA NA Nephropathy NA

198 GAS6 7.52503 9.818395 8.479805 8.975413 NA NA NA Nephropathy NA

199 GCG 1.132528 5.568321 3.05203 4.137392 NA NA NA Nephropathy NA

200 GCK 3.003543 6.517393 4.366613 5.292621 NA NA NA Nephropathy Neuropathy

201 GCKR 5.094638 7.489403 6.327679 6.856691 Cardiovascular NA NA NA NA diseases 202 GDF15 2.583365 6.304086 3.569199 4.431494 Cardiovascular NA NA Nephropathy NA diseases 203 GFAP 2.270427 4.58027 3.127321 3.662665 NA NA NA NA Neuropathy

204 GFPT1 6.782755 8.761425 7.674148 8.194142 NA NA NA Nephropathy NA

205 GFPT2 3.590627 7.50948 5.764212 6.675871 NA NA NA Nephropathy NA

206 GGT1 7.571782 8.950075 7.931878 8.257324 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 207 GHR 0.679657 6.055266 3.141845 4.642321 NA NA NA Nephropathy NA

208 GIP 2.510394 6.456772 3.604226 4.655978 Cardiovascular NA Atherosclerosis NA Neuropathy diseases 209 GIPR 2.617258 6.911614 4.14937 5.127715 NA Retinopathy NA NA Neuropathy

210 GK 4.888061 8.874641 6.775945 7.406682 Cardiovascular NA NA NA NA diseases

211 GLO1 10.37621 11.35707 10.81215 11.02044 NA NA Atherosclerosis Nephropathy Neuropathy

212 GLP1R 6.940776 8.428574 7.410023 7.811685 Cardiovascular NA NA NA Neuropathy diseases 213 GLUL 8.365377 10.5997 9.236404 9.915374 Cardiovascular NA NA NA NA diseases 214 GNB3 6.214359 7.965265 6.915482 7.327243 NA NA NA Nephropathy NA

215 GPC5 0.617403 6.425303 2.885042 4.164098 NA NA NA Nephropathy NA

216 GPX1 11.74613 13.54304 12.45141 12.88731 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 217 GRB2 9.145623 11.09686 10.11606 10.50122 NA Retinopathy NA NA NA

218 GREM1 0.979859 6.943341 4.087674 5.397189 NA NA NA Nephropathy NA

219 GSTM1 7.020131 9.794474 8.330759 8.907639 NA Retinopathy Atherosclerosis Nephropathy NA

220 GSTT1 3.845184 8.047889 5.186233 6.305133 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 221 GYS1 7.871581 9.250803 8.564777 8.911521 Cardiovascular NA NA NA NA diseases 222 HCN2 1.842932 7.143079 4.108265 5.449467 NA NA NA NA Neuropathy

223 HDAC4 7.20011 8.789875 7.867209 8.171464 NA NA NA Nephropathy NA

224 HDAC9 6.484647 8.764281 7.381468 7.874992 NA NA Atherosclerosis NA NA

225 HFE 5.368042 7.918004 6.810278 7.398177 NA Retinopathy NA Nephropathy NA

226 HGF 3.354404 7.460042 5.421897 6.313515 NA NA Atherosclerosis Nephropathy Neuropathy

227 HHEX 8.17756 10.14719 9.151245 9.55091 Cardiovascular NA NA Nephropathy NA diseases 228 HIF1A 10.87303 12.59429 11.61792 11.96342 Cardiovascular NA NA Nephropathy NA diseases 229 HLA-A 14.31787 15.41993 14.6997 14.9853 NA NA NA Nephropathy NA

230 HLA- 3.278037 12.2045 7.147905 9.775908 NA NA NA Nephropathy NA DQA1 231 HMGA2 2.463489 7.019532 5.033168 6.163071 NA NA NA Nephropathy NA

232 HMGB1 10.8024 12.85964 11.64943 12.12301 Cardiovascular Retinopathy NA Nephropathy NA diseases 233 HMGCS2 2.718059 6.348583 3.903528 4.791373 NA NA NA Nephropathy NA

234 HMOX1 8.085758 10.10764 9.085462 9.554879 NA NA NA Nephropathy NA

235 HNF1A 4.00321 7.428601 5.479961 6.404419 NA NA NA Nephropathy NA

236 HNF1B 5.599925 8.598146 6.564462 7.32486 Cardiovascular NA NA NA NA diseases 237 HNF4A 2.156248 8.053906 5.671922 6.724617 Cardiovascular NA NA NA NA diseases 238 HP 4.27679 9.810106 7.091749 8.229285 Cardiovascular NA Atherosclerosis NA NA diseases 239 HRH1 2.546134 6.890076 4.21345 5.22115 NA NA NA NA Neuropathy

240 HSPA1A 8.644075 12.30742 10.91218 11.60412 NA NA NA Nephropathy NA

241 HSPA1B 5.080721 8.453866 6.505199 7.189023 NA NA NA Nephropathy NA

242 HSPA5 11.11965 12.7663 11.60533 11.96121 NA NA NA NA Neuropathy

243 HSPB1 8.439816 10.00837 8.988823 9.414864 NA NA NA Nephropathy NA

244 HSPG2 2.940762 7.003505 4.17639 5.364511 NA NA NA Nephropathy NA

245 HTR2A 3.612696 7.951941 6.024913 6.760833 NA NA NA Nephropathy NA

246 HYOU1 9.008833 10.56064 9.692943 10.01844 NA NA NA Nephropathy Neuropathy

247 ICAM1 7.009224 10.43826 8.393573 9.095021 NA NA Atherosclerosis Nephropathy NA

248 ID1 6.523788 11.33881 7.998512 9.165679 NA NA NA Nephropathy NA

249 IFNG 5.022143 8.014401 6.595227 7.21995 NA NA NA Nephropathy Neuropathy

250 IGF1 2.964193 7.284691 4.217505 5.34777 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 251 IGF1R 6.615888 9.085137 7.390257 7.903838 NA Retinopathy NA NA NA

252 IGF2 3.654553 7.215747 5.139696 6.037479 NA Retinopathy NA Nephropathy Neuropathy

253 IGFBP1 2.414102 6.888923 3.890302 5.009392 NA NA NA Nephropathy NA

254 IGFBP3 4.80913 8.737926 6.333068 7.298299 NA NA NA Nephropathy NA

255 IGFBP5 2.643778 7.447872 3.488824 4.483409 NA NA NA NA Neuropathy

256 IGFBP7 5.519036 9.822363 7.753548 8.698486 NA NA NA Nephropathy NA

257 IL10 2.384213 7.168749 4.701694 5.808533 NA NA NA Nephropathy Neuropathy

258 IL17A 2.456746 7.074114 4.262567 5.297713 NA Retinopathy NA Nephropathy NA

259 IL18 2.65881 8.000439 5.682543 6.76222 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 260 IL1B 7.188535 11.59303 8.386515 9.306264 Cardiovascular Retinopathy NA Nephropathy NA diseases 261 IL1RN 7.876065 10.65511 8.711735 9.298135 NA NA NA Nephropathy NA

262 IL4 3.693446 7.327003 5.35695 6.215146 NA NA NA NA Neuropathy

263 IL6 5.779367 8.256834 6.350617 6.958991 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

264 ILK 9.686751 11.12684 10.19135 10.56623 NA NA NA Nephropathy NA

265 INS 2.465818 4.586518 3.169523 3.654575 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 266 IRAK1 10.35504 11.61731 10.60989 10.89676 NA NA NA NA Neuropathy

267 IRS1 6.115814 8.075566 6.875425 7.371444 NA Retinopathy NA NA NA

268 IRS2 9.111041 10.86196 9.685904 10.06952 NA NA Atherosclerosis Nephropathy Neuropathy

269 ITGA2 4.388072 7.415581 5.670339 6.48829 NA Retinopathy NA NA NA

270 ITGAM 5.428713 8.147065 6.545355 7.061673 NA Retinopathy NA Nephropathy NA

271 ITGB3 5.275438 8.476325 6.831997 7.631218 NA Retinopathy NA NA NA

272 JAK2 3.494206 8.478411 6.647517 7.598978 NA NA NA Nephropathy NA

273 KCNQ1 1.665658 6.723657 3.317011 4.516653 NA NA NA Nephropathy NA

274 KDM1A 8.297492 9.704572 8.87997 9.217603 NA Retinopathy NA NA NA

275 KL 1.030048 6.023674 3.752388 4.803083 NA NA NA Nephropathy NA

276 KLF10 10.00249 12.58904 10.79607 11.44601 NA NA NA Nephropathy NA

277 KLF6 9.989906 11.97261 10.55019 11.08727 NA NA NA Nephropathy NA

278 L1CAM 3.509362 7.592017 4.799382 6.019337 NA Retinopathy NA NA NA

279 LAMC1 4.33181 7.625548 6.142098 6.968759 NA NA NA Nephropathy NA

280 LDLR 2.925702 7.227101 4.43784 5.690458 Cardiovascular NA Atherosclerosis NA NA diseases 281 LEP 2.284905 7.060299 3.950694 5.238156 NA NA Atherosclerosis NA Neuropathy

282 LIMK2 6.83348 9.22945 7.327481 7.82323 NA NA NA Nephropathy NA

283 LMNA 7.34485 9.955779 8.066612 8.599491 NA NA NA Nephropathy NA

284 LPA 1.951652 7.415126 3.858947 5.081881 Cardiovascular NA Atherosclerosis NA NA diseases 285 LPL 1.966215 7.570826 3.469724 4.719111 Cardiovascular NA Atherosclerosis Nephropathy Neuropathy diseases 286 LPO 2.183922 8.053549 5.006654 6.222725 NA Retinopathy NA NA NA

287 LRP2 3.801773 7.627479 5.478353 6.247264 NA NA NA Nephropathy NA

288 LTA 3.526215 7.036114 4.651227 5.443028 NA NA NA Nephropathy NA

289 MALT1 8.177752 10.14297 9.301328 9.726747 NA NA NA Nephropathy NA

290 MAP3K5 8.071897 9.783237 9.041514 9.435005 Cardiovascular NA NA Nephropathy NA diseases 291 MAPK1 7.911358 9.654739 8.686795 9.089284 NA NA NA Nephropathy Neuropathy

292 MAPK14 9.252345 11.02201 10.01065 10.40485 NA NA NA Nephropathy NA

293 MAPK7 4.893154 8.482828 6.005446 6.806331 NA Retinopathy NA NA NA

294 MBL2 0.558622 5.078093 2.364107 3.668367 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 295 MBP 5.635849 8.393612 6.930981 7.475884 NA NA NA NA Neuropathy

296 MCAM 2.877111 9.050084 5.847686 6.893277 NA NA NA Nephropathy NA

297 MEP1B 3.592785 6.829206 4.956492 5.805336 NA NA NA Nephropathy NA

298 MIF 11.20906 12.38486 11.58266 11.91109 NA NA Atherosclerosis Nephropathy Neuropathy

299 MME 2.985133 7.537423 4.945529 6.033328 NA NA NA NA Neuropathy

300 MMP14 6.978653 9.144628 7.694714 8.274327 NA NA NA Nephropathy NA

301 MMP16 1.703693 6.62325 4.657381 5.779102 NA NA NA Nephropathy NA

302 MMP2 5.260306 7.620464 6.454501 6.97883 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 303 MMP24 3.191326 7.56342 5.42419 6.394057 NA NA NA Nephropathy NA

304 MMP9 6.919215 10.22086 7.906768 8.556225 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 305 MOK 4.730599 7.155012 5.638641 6.287505 NA NA Atherosclerosis Nephropathy NA

306 MPO 4.448341 8.382796 5.891318 6.920932 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 307 MRPL28 6.296141 9.397724 8.362012 8.894205 NA Retinopathy NA NA NA

308 MSH2 7.519309 9.448318 8.368511 8.840434 Cardiovascular NA NA NA NA diseases 309 MTHFR 4.472611 7.262453 5.633175 6.38761 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

310 MTOR 5.982975 7.944615 7.12327 7.569594 NA NA NA Nephropathy NA

311 MYD88 11.47485 12.72778 11.74503 12.01409 NA NA NA Nephropathy NA

312 MYH9 10.18495 11.95847 11.13503 11.49533 NA NA NA Nephropathy NA

313 NAGLU 7.198443 8.365769 7.729438 8.006002 Cardiovascular Retinopathy NA NA NA diseases 314 NAMPT 6.994846 10.44188 8.539406 9.327105 Cardiovascular NA NA NA NA diseases 315 NCALD 5.788733 8.685485 7.210081 7.820456 NA NA NA Nephropathy NA

316 NCF2 10.3524 13.15431 11.85946 12.41412 NA NA NA Nephropathy NA

317 NDUFS3 10.042 10.7969 10.37637 10.55859 NA NA NA Nephropathy NA

318 NEDD4L 5.048476 7.577047 6.215044 6.786135 NA NA NA Nephropathy NA

319 NFE2 7.88506 10.55984 8.54892 9.181783 NA NA NA Nephropathy NA

320 NFE2L2 8.982115 10.92153 9.80682 10.20882 NA Retinopathy NA Nephropathy Neuropathy

321 NFKBIA 10.93074 13.95023 12.44835 13.14835 NA NA NA Nephropathy NA

322 NGF 3.46424 7.144027 4.857509 5.887293 NA NA NA Nephropathy Neuropathy

323 NGFR 2.559243 8.193804 3.717597 4.684669 NA NA NA NA Neuropathy

324 NLRP3 6.622809 9.743806 7.65887 8.196871 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 325 NME2 11.21713 12.19676 11.59396 11.84015 NA Retinopathy NA NA NA

326 NOS1 6.399492 8.082856 6.939049 7.35285 NA Retinopathy NA Nephropathy Neuropathy

327 NOS2 4.149324 7.628606 5.920426 6.674677 NA Retinopathy NA Nephropathy NA

328 NOS3 2.125708 6.517168 3.694302 4.636403 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 329 NOV 4.001943 7.699304 5.784619 6.706434 NA NA NA Nephropathy NA

330 NOX1 0.923514 5.749777 2.29632 3.271846 NA NA NA Nephropathy NA

331 NPHS1 2.441413 7.038282 3.792447 4.929142 NA NA NA Nephropathy NA

332 NPPA 6.459671 8.935605 7.704221 8.242101 Cardiovascular NA NA NA NA diseases 333 NPY 4.126794 7.13513 5.436803 6.179813 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

334 NPY2R 2.772296 7.501366 5.037736 6.021388 Cardiovascular NA NA NA NA diseases 335 NPY5R 3.300796 7.707097 5.396264 6.23701 Cardiovascular NA NA NA NA diseases 336 NQO1 2.98059 6.865579 3.859908 4.658545 Cardiovascular NA Atherosclerosis NA NA diseases 337 NR1H3 5.332041 7.815093 6.671737 7.218458 NA NA NA Nephropathy NA

338 NR3C2 6.426758 8.457478 7.466199 7.982433 Cardiovascular NA NA NA NA diseases 339 NRF1 6.914606 8.741097 7.73879 8.173725 NA NA NA NA Neuropathy

340 NSA2 12.19223 13.34406 12.53622 12.81809 NA NA NA Nephropathy NA

341 NTF3 4.661843 7.341304 5.064337 5.807665 NA NA NA NA Neuropathy

342 NTS 1.221857 6.531255 3.322488 4.791523 Cardiovascular NA NA NA NA diseases

343 NUCB2 8.85534 10.65196 9.532379 10.02579 Cardiovascular Retinopathy NA NA NA diseases 344 ONECUT 2.230574 6.526973 3.863108 4.947082 NA NA NA Nephropathy NA 1 345 OSM 2.630155 6.77838 3.912324 4.791287 NA NA NA Nephropathy NA

346 OXT 3.59392 7.41399 4.846439 5.774344 Cardiovascular NA NA NA NA diseases 347 P2RX3 2.349174 7.137613 3.857845 4.984876 NA NA NA NA Neuropathy

348 P2RY1 2.831466 6.873854 5.07975 6.032625 NA NA NA NA Neuropathy

349 P2RY2 4.013875 8.121854 5.351278 6.49675 NA NA NA NA Neuropathy

350 PARP1 8.875278 10.11971 9.380032 9.680864 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 351 PC 3.600385 7.535591 5.534006 6.431008 NA NA NA Nephropathy NA

352 PDE5A 2.073476 6.611865 3.933311 5.109593 NA NA NA Nephropathy Neuropathy

353 PDGFA 2.814395 7.519078 5.42291 6.481826 NA NA NA Nephropathy NA

354 PDGFB 2.260874 6.823894 3.560882 4.541265 NA NA NA Nephropathy NA

355 PDGFRB 3.742492 7.697474 5.246426 6.209259 NA NA NA Nephropathy NA

356 PDHX 7.648174 8.880646 8.153564 8.497926 NA Retinopathy NA NA NA

357 PDK1 4.034038 9.002824 6.504676 7.63969 NA NA NA Nephropathy NA

358 PDPK1 7.754924 9.521456 8.579601 9.0128 NA NA NA Nephropathy NA

359 PEBP1 8.715692 9.860146 9.213986 9.512169 NA NA NA Nephropathy NA

360 PECAM1 9.681682 11.72421 10.41246 10.93648 NA NA NA NA Neuropathy

361 PFKFB2 2.652913 7.698928 4.394315 5.733077 NA NA NA Nephropathy NA

362 PGF 2.940104 7.237296 4.172836 5.142141 Cardiovascular NA NA NA NA diseases 363 PHACTR 4.13842 8.368584 6.060624 7.033785 Cardiovascular NA NA NA NA 1 diseases 364 PICK1 5.008786 8.443938 6.654067 7.406539 NA NA NA Nephropathy NA

365 PIGF 8.09094 9.654755 8.754514 9.122671 NA Retinopathy NA NA NA

366 PIK3CA 8.173458 11.17641 9.30275 9.750812 NA NA NA Nephropathy NA

367 PIP 3.443233 7.624463 4.946255 6.090881 NA NA NA Nephropathy NA

368 PLA2G2 3.361487 8.157251 5.077635 6.222078 NA NA Atherosclerosis NA NA A 369 PLIN1 3.011659 7.206495 4.35462 5.303642 Cardiovascular NA NA NA NA diseases 370 PLIN2 9.008073 10.98642 9.96826 10.33095 Cardiovascular NA NA NA NA diseases 371 PLN 1.310623 7.151462 2.857054 4.222442 Cardiovascular NA NA NA NA diseases 372 PLTP 2.695223 7.040603 4.436969 5.635927 NA NA Atherosclerosis NA NA

373 PLXDC1 6.71702 8.876541 7.684248 8.150336 NA Retinopathy NA NA NA

374 PMP22 2.858557 7.197251 5.235188 6.269567 NA NA NA NA Neuropathy

375 POLR2D 7.320095 9.545104 8.22286 8.659724 NA Retinopathy NA NA NA

376 POMC 3.623872 7.191586 4.766915 5.755631 Cardiovascular NA NA NA Neuropathy diseases 377 PON1 2.885311 7.780337 4.948827 6.003787 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 378 PON2 6.863563 9.455939 7.877306 8.3716 NA NA Atherosclerosis Nephropathy NA

379 PON3 2.455589 7.787218 4.147919 5.385948 Cardiovascular NA Atherosclerosis NA NA diseases 380 POSTN 2.135274 7.803501 4.923836 6.017422 NA Retinopathy NA Nephropathy NA

381 PPARA 4.116256 7.692323 5.920041 6.709396 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 382 PPARG 2.015586 5.835008 3.494392 4.439541 NA Retinopathy Atherosclerosis Nephropathy NA

383 PPIA 14.38813 15.41414 14.63063 14.89323 Cardiovascular NA NA Nephropathy NA diseases 384 PPY 4.241314 7.735902 5.876977 6.73265 NA NA NA NA Neuropathy

385 PRCP 10.07499 11.46433 10.7753 11.03487 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 386 PRDX1 9.681664 12.28562 11.38948 11.84643 Cardiovascular NA NA NA NA diseases

387 PRDX2 6.51983 8.500811 7.364406 7.780531 Cardiovascular NA NA NA NA diseases 388 PRDX4 9.067881 9.918274 9.265911 9.516691 Cardiovascular NA NA NA NA diseases 389 PRDX6 10.60745 11.98145 10.99189 11.35736 Cardiovascular NA NA NA NA diseases 390 PRKAA1 6.477811 9.680437 7.604738 8.289996 NA NA NA Nephropathy NA

391 PRKCB 10.01604 11.05479 10.42233 10.70258 NA NA NA Nephropathy Neuropathy

392 PRKCE 4.378357 7.763542 5.959378 6.671705 NA NA NA Nephropathy NA

393 PRKG1 0.150585 4.948961 1.828289 2.942303 NA NA NA NA Neuropathy

394 PRMT2 9.492979 10.58035 9.951748 10.26054 NA NA Atherosclerosis NA NA

395 PROC 2.282262 7.170727 3.545437 4.678386 NA NA NA Nephropathy NA

396 PROM1 2.44657 6.19682 4.508133 5.525909 NA NA NA NA Neuropathy

397 PSIP1 8.477002 10.94278 9.96121 10.49408 NA Retinopathy NA NA NA

398 PSMA6 11.45811 12.84054 12.10402 12.40997 Cardiovascular NA NA Nephropathy NA diseases 399 PSMD9 9.084818 10.35021 9.786658 10.06304 NA Retinopathy NA Nephropathy Neuropathy

400 PTEN 10.02627 11.30089 10.55135 10.81708 NA NA NA Nephropathy Neuropathy

401 PTGDS 5.168123 9.716814 7.566746 8.381638 NA NA Atherosclerosis Nephropathy NA

402 PTGER1 4.114136 8.317368 5.445346 6.379762 NA NA NA Nephropathy NA

403 PTGER4 3.462646 8.56216 6.394473 7.644874 NA NA NA Nephropathy NA

404 PTGES 4.255248 8.168749 5.744009 6.748948 NA NA NA Nephropathy NA

405 PTGS2 4.586423 10.35814 7.403281 8.448901 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 406 PTH 1.134467 5.733621 2.683168 3.927487 Cardiovascular NA NA Nephropathy NA diseases 407 PTH1R 3.531785 8.101084 6.472005 7.335566 NA NA NA Nephropathy NA

408 PTPN1 8.25161 9.997959 8.891466 9.317665 Cardiovascular NA NA Nephropathy NA diseases 409 PTX3 5.91646 8.832695 6.868774 7.487547 NA Retinopathy Atherosclerosis Nephropathy NA

410 PVT1 2.890791 7.432456 5.300118 6.403631 NA NA NA Nephropathy NA

411 RAF1 9.996759 11.04044 10.27003 10.52231 NA Retinopathy NA Nephropathy NA

412 RARRES2 3.027905 8.278805 4.337536 5.310722 Cardiovascular NA NA NA NA diseases 413 RBP1 3.962722 7.057165 5.210233 6.120149 NA Retinopathy NA NA NA

414 RBP4 1.277646 5.606025 3.298913 4.219203 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 415 RCAN1 5.399344 8.968713 7.742467 8.387737 NA NA NA Nephropathy NA

416 REG1A 2.759518 7.125977 3.646219 4.551455 NA NA NA Nephropathy NA

417 RELA 9.034774 11.33088 9.62564 10.10443 NA Retinopathy NA Nephropathy NA

418 REN 2.318625 6.208963 4.251779 5.090297 Cardiovascular NA Atherosclerosis NA NA diseases 419 RGN 2.460645 7.041437 4.338563 5.431317 NA NA NA Nephropathy NA

420 RHO 3.632569 7.531269 4.887099 5.880008 NA Retinopathy NA NA NA

421 RHOA 12.88661 13.91912 13.33213 13.55293 NA NA NA NA Neuropathy

422 RHOD 3.128501 7.07615 3.975933 4.799063 NA NA NA Nephropathy NA

423 ROCK1 10.31961 11.72201 11.12752 11.46059 NA NA NA Nephropathy NA

424 ROCK2 6.493937 9.134964 8.217095 8.643799 NA NA Atherosclerosis NA NA

425 RPS12 14.60121 15.86831 15.04342 15.32173 NA NA NA Nephropathy NA

426 RPS6 14.56278 15.4903 14.8832 15.08032 NA NA NA Nephropathy NA

427 RREB1 8.874889 10.61744 9.348516 9.709747 NA NA NA Nephropathy NA

428 RTN1 5.685206 9.674386 8.144043 8.909415 NA NA NA Nephropathy NA

429 S100A12 10.82041 13.7991 11.56911 12.36178 Cardiovascular Retinopathy NA NA NA diseases 430 SARDH 1.916742 5.819049 3.040884 4.035001 NA Retinopathy NA NA NA

431 SCARB1 6.376418 8.081469 7.115376 7.572967 NA NA Atherosclerosis NA NA

432 SELE 1.287457 6.106582 3.399802 4.469555 NA NA NA Nephropathy NA

433 SEMA3A 3.69761 7.517807 6.056189 6.814322 NA NA NA Nephropathy NA

434 SERPINB 3.003533 5.540166 3.999777 4.596899 NA NA NA Nephropathy NA 7 435 SERPINE 3.853695 7.37654 5.091033 5.874756 NA NA NA Nephropathy NA 1 436 SERPINF 7.835085 11.20363 8.557183 9.194253 NA Retinopathy NA Nephropathy Neuropathy 1 437 SERPINF 4.453367 7.559167 5.963562 6.712091 NA NA NA Nephropathy NA 2 438 SFI1 7.192277 9.61621 8.397413 8.885843 NA NA NA Nephropathy NA

439 SGK1 9.045577 12.32907 10.59915 11.37634 NA NA NA Nephropathy NA

440 SHBG 3.296901 5.814618 4.237067 4.912809 Cardiovascular NA NA NA NA diseases 441 SLC12A3 2.540619 5.426068 3.589361 4.299858 NA NA NA Nephropathy NA

442 SLC22A6 3.003049 6.027322 4.262746 4.875711 NA NA NA Nephropathy NA

443 SLC2A1 3.479028 7.651536 5.106722 6.319362 Cardiovascular NA NA Nephropathy NA diseases 444 SLC2A2 0.462285 3.53993 1.795335 2.598461 NA NA NA Nephropathy NA

445 SLC2A3 8.241291 10.45478 9.138074 9.731442 NA NA NA NA Neuropathy

446 SLC2A4 2.377418 7.173602 4.539294 5.627919 Cardiovascular NA NA Nephropathy Neuropathy diseases 447 SLC5A2 3.675986 7.605358 5.950982 6.823372 Cardiovascular NA NA NA NA diseases 448 SLC9A1 5.393387 8.855885 7.421679 8.072499 NA NA NA Nephropathy NA

449 SMAD1 1.559822 7.20253 4.612602 5.661859 NA NA NA Nephropathy NA

450 SMAD7 6.899868 9.899049 7.79445 8.373996 NA NA NA Nephropathy NA

451 SMG1 5.160058 8.150465 6.419178 7.076776 NA Retinopathy NA NA NA

452 SMPD1 5.798562 9.276898 8.388342 8.969326 NA Retinopathy NA NA NA

453 SOCS1 2.478495 5.213766 3.678947 4.393374 NA NA NA Nephropathy NA

454 SOCS2 4.071214 8.679596 7.07171 7.891202 NA NA NA Nephropathy NA

455 SOCS3 5.164898 8.619485 6.469064 7.072893 NA Retinopathy NA Nephropathy NA

456 SOD1 11.64597 12.56507 12.03263 12.28311 NA Retinopathy NA Nephropathy NA

457 SOD2 3.584126 7.73683 5.802251 6.648524 NA Retinopathy NA NA Neuropathy

458 SORBS2 2.604703 6.727894 4.516082 5.402254 NA NA NA Nephropathy NA

459 SOX9 2.736387 6.990686 4.496707 5.656112 NA NA NA Nephropathy NA

460 SPARC 6.556239 11.20592 9.219147 10.09565 NA Retinopathy NA Nephropathy NA

461 SPP1 2.80434 7.088759 4.403879 5.586153 Cardiovascular Retinopathy NA Nephropathy NA diseases 462 SRC 4.518193 8.283776 5.260886 6.123631 NA NA NA Nephropathy NA

463 SREBF1 5.456935 9.103227 7.599827 8.198913 NA NA NA Nephropathy Neuropathy

464 SRGN 12.37937 14.54351 13.15887 13.70923 NA Retinopathy NA NA NA

465 SST 1.787062 7.437019 4.560108 5.934716 NA Retinopathy NA Nephropathy NA

466 STAT1 10.20936 13.01084 11.48697 12.01943 NA NA NA Nephropathy NA

467 STAT3 10.41432 11.74415 11.05496 11.37238 NA Retinopathy NA Nephropathy NA

468 STAT5A 8.352164 9.710861 8.837752 9.122015 NA NA NA Nephropathy NA

469 STK11 4.0366 7.508446 5.90492 6.724 NA NA NA Nephropathy NA

470 SUMO4 9.218658 10.58227 9.753725 10.0708 Cardiovascular NA NA Nephropathy NA diseases 471 TACR1 4.55 7.679524 5.902585 6.619475 Cardiovascular NA NA NA NA diseases 472 TCF7L2 3.741564 8.692245 6.439252 7.496913 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 473 TF 3.369027 7.138435 4.643312 5.562774 NA NA NA Nephropathy NA

474 TFAM 7.567925 9.344451 8.234367 8.698697 NA NA NA NA Neuropathy

475 TGFB1 3.553709 7.884232 5.01874 6.095089 Cardiovascular NA NA Nephropathy NA diseases 476 TGFBR1 2.945055 8.046329 5.355231 6.665087 NA NA NA Nephropathy NA

477 TH 3.1511 7.527907 5.031656 5.982632 NA Retinopathy NA NA Neuropathy

478 THBD 3.662748 9.713267 6.333783 7.303397 NA NA NA Nephropathy NA

479 THBS1 2.826446 7.272186 3.79536 4.697092 NA Retinopathy NA Nephropathy NA

480 THBS2 2.697816 7.208138 4.917555 6.048847 NA NA NA Nephropathy NA

481 TIMM44 3.545071 8.606109 6.847302 7.803822 NA NA NA Nephropathy NA

482 TIMP1 10.33609 12.35943 11.43815 11.85105 NA Retinopathy NA NA NA

483 TIMP2 7.337127 10.31473 8.720914 9.243447 NA NA NA Nephropathy NA

484 TIMP3 1.658034 7.36205 3.81347 5.019138 NA Retinopathy Atherosclerosis Nephropathy NA

485 TKT 10.74033 12.81932 11.61462 12.00701 NA NA NA Nephropathy Neuropathy

486 TLR2 9.308278 12.25961 10.06489 10.66513 NA NA NA Nephropathy NA

487 TNF 4.188169 9.036829 6.573591 7.668911 NA Retinopathy NA Nephropathy Neuropathy

488 TNFAIP8 10.24833 11.9904 10.94513 11.36011 NA NA NA Nephropathy NA

489 TNFRSF1 -0.0648 7.240433 3.304667 4.97322 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy 1B diseases 490 TNFRSF1 10.16622 11.57117 10.67799 11.03177 NA NA NA NA Neuropathy B 491 TPM1 7.362793 8.887178 7.860812 8.251096 Cardiovascular NA NA NA NA diseases 492 TRAF6 6.495544 8.840355 7.593337 8.06054 NA NA NA NA Neuropathy

493 TRH 3.75941 7.520053 5.07526 6.111092 NA NA NA NA Neuropathy

494 TRPA1 4.640538 8.146013 5.679381 6.499513 NA NA NA NA Neuropathy

495 TRPC1 2.739539 7.208324 4.695768 5.935849 NA NA NA Nephropathy NA

496 TRPC6 2.09789 6.447979 4.069237 5.301553 NA NA Atherosclerosis Nephropathy NA

497 TSC1 8.213505 9.538474 8.809555 9.112844 NA NA NA Nephropathy NA

498 TSC2 3.751174 7.711896 5.146206 6.168613 NA NA NA Nephropathy NA

499 TSC22D1 8.825126 11.03461 9.760765 10.26365 NA NA NA Nephropathy NA

500 TSPO 11.1783 12.96681 11.79162 12.2242 NA NA NA NA Neuropathy

501 TUBB3 8.36654 9.83426 8.918765 9.264663 NA Retinopathy NA NA NA

502 TXN 9.536808 11.075 10.28218 10.58912 Cardiovascular NA Atherosclerosis NA NA diseases 503 TXNIP 12.99857 14.74322 13.9444 14.26547 NA Retinopathy Atherosclerosis Nephropathy NA

504 UCP2 9.725803 11.964 10.91421 11.38599 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

505 UMOD 3.075817 7.074485 4.519596 5.566753 NA NA NA Nephropathy NA

506 UNC13A 2.657766 5.584732 3.487797 4.291856 NA NA NA NA Neuropathy

507 UNC13B 4.611542 7.309557 6.132913 6.760336 NA NA NA Nephropathy NA

508 UNC5B 4.190815 7.891012 5.047382 5.938632 NA NA NA Nephropathy NA

509 USF2 8.528663 10.28098 9.252484 9.61134 NA NA NA Nephropathy NA

510 UTRN 8.202263 9.882408 8.883352 9.363035 NA NA NA Nephropathy NA

511 VCAM1 5.05082 7.314193 5.698312 6.223003 Cardiovascular NA Atherosclerosis NA NA diseases 512 VDAC1 8.438952 10.26619 9.339006 9.74098 NA NA NA Nephropathy NA

513 VDAC2 11.07218 12.0438 11.56379 11.78636 NA NA NA Nephropathy NA

514 VDR 4.645916 8.411807 6.230642 7.168448 Cardiovascular Retinopathy NA Nephropathy NA diseases 515 VEGFA 6.140717 8.760976 7.430043 8.056921 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

516 VEGFC 3.688733 7.825744 5.518619 6.290995 NA Retinopathy NA NA NA

517 VIP 1.206857 6.580616 2.808075 3.956808 NA NA NA NA Neuropathy

518 VWF 3.625687 7.224325 4.575963 5.418058 Cardiovascular NA NA Nephropathy Neuropathy diseases

519 WFS1 6.225914 8.083004 7.1229 7.549365 NA NA NA Nephropathy NA

520 WT1 1.783014 5.695381 3.062283 3.984848 NA NA NA Nephropathy NA

521 XBP1 9.853939 11.57257 10.49098 10.81557 NA NA NA Nephropathy NA

522 XIAP 4.11528 7.356724 5.638115 6.3934 NA NA NA NA Neuropathy

523 XRCC1 6.979719 8.483849 7.663985 8.057096 Cardiovascular Retinopathy NA NA NA diseases 524 ZEB2 5.569875 8.560382 7.211434 7.925879 NA NA NA Nephropathy NA

Table A.3: table for heart tissue

Genes Actual Actual 99% CI 99% CI complication1 complication2 complication3 complication4 complication5 Min Max Min Max 1 ABCA1 6.607734 8.182975 7.0266 7.513407 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 2 ABCG1 6.12564 7.264937 6.463821 6.863875 Cardiovascular NA Atherosclerosis NA NA diseases 3 ABO 6.5957 7.318915 6.742627 6.980978 Cardiovascular NA NA NA NA diseases 4 ACACB 7.191682 8.568073 7.945201 8.388229 NA NA NA Nephropathy NA

5 ACAT1 9.231646 10.63558 9.651299 10.06719 NA NA Atherosclerosis NA NA

6 ACE 6.235947 6.577995 6.335509 6.457331 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 7 ACE2 5.933142 7.300766 6.639603 7.104121 Cardiovascular NA NA Nephropathy NA diseases 8 ACSL1 8.986491 10.37018 9.439298 9.859573 NA NA Atherosclerosis NA NA

9 ACVRL1 7.174563 7.920436 7.413085 7.683358 NA NA NA Nephropathy NA

10 ADAM10 8.75615 9.917656 9.267476 9.631762 NA NA NA Nephropathy NA

11 ADAM17 7.310071 8.190084 7.615309 7.92497 NA NA Atherosclerosis Nephropathy NA

12 ADAMTS1 6.517079 7.32392 6.779931 7.085375 NA NA NA Nephropathy NA 3 13 ADCYAP1 6.075849 7.051814 6.479344 6.805152 NA Retinopathy NA Nephropathy NA

14 ADH1B 7.731806 10.12232 8.710315 9.644666 NA NA NA Nephropathy Neuropathy

15 ADIPOQ 5.294588 7.758768 5.902079 6.559811 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 16 ADIPOR1 9.167105 9.921163 9.419395 9.672808 Cardiovascular NA NA NA NA diseases 17 ADK 7.921934 8.729656 8.158911 8.449584 NA Retinopathy NA NA NA

18 ADM 6.680247 8.345775 7.234596 7.737601 NA Retinopathy NA Nephropathy Neuropathy

19 ADRA2B 6.44073 7.204816 6.707867 6.936689 NA NA NA NA Neuropathy

20 AGER 6.139243 6.736555 6.268127 6.422369 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 21 AGT 8.495593 9.572777 8.821655 9.210892 NA NA NA Nephropathy Neuropathy

22 AGTR1 6.712843 7.77637 6.965594 7.346043 NA NA NA Nephropathy NA

23 AHSA1 8.307996 9.470444 8.483813 8.850015 Cardiovascular Retinopathy NA Nephropathy NA diseases 24 AHSG 5.19697 5.767822 5.37369 5.551531 Cardiovascular Retinopathy NA Nephropathy NA diseases 25 AKR1B1 9.385535 10.62192 9.873964 10.20004 NA Retinopathy NA Nephropathy Neuropathy

26 AKR1B10 4.605609 5.208876 4.715757 4.939313 NA NA NA Nephropathy NA

27 AKT1 9.180391 9.857906 9.36287 9.582258 Cardiovascular Retinopathy NA Nephropathy NA diseases 28 ALB 4.656226 5.278543 4.789895 4.968998 NA NA Atherosclerosis Nephropathy Neuropathy

29 ALDH1A1 7.148491 9.117087 8.062604 8.763643 NA NA NA Nephropathy NA

30 ALDH2 10.29325 11.46385 10.70936 11.12434 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 31 ALOX5AP 6.936611 8.295956 7.331679 7.760604 NA NA Atherosclerosis Nephropathy NA

32 ALPK1 5.685198 6.591976 6.111288 6.368827 Cardiovascular NA NA NA NA diseases 33 ALPL 6.333864 7.971286 6.813471 7.277916 NA NA NA Nephropathy NA

34 AMBP 5.88062 6.792742 6.127699 6.387752 NA NA NA Nephropathy NA

35 ANG 6.641774 7.857735 7.07128 7.403916 NA NA NA Nephropathy NA

36 ANGPT2 6.297868 8.954432 7.051526 7.802197 NA Retinopathy NA NA NA

37 ANGPTL2 7.715528 9.439888 8.291434 8.806314 NA NA Atherosclerosis Nephropathy NA

38 ANGPTL4 6.216517 8.586196 6.694126 7.347005 NA Retinopathy NA Nephropathy NA

39 AOC2 5.409712 6.359813 5.768635 6.012157 NA NA NA Nephropathy NA

40 AOC3 8.595547 9.90022 8.927586 9.323474 NA Retinopathy NA NA NA

41 APC 7.001664 8.209358 7.436776 7.719137 NA NA NA Nephropathy NA

42 API5 7.649248 8.307502 7.882342 8.110083 NA Retinopathy NA NA NA

43 APLNR 6.823423 8.51082 7.294044 7.890249 NA NA NA Nephropathy NA

44 APOA1 4.789719 6.161343 5.096125 5.446095 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 45 APOB 6.620949 7.815365 6.929334 7.319808 Cardiovascular Retinopathy NA NA Neuropathy diseases 46 APOC1 5.703504 7.161528 6.183316 6.614166 NA NA NA Nephropathy NA

47 APOC3 5.259224 6.052639 5.558656 5.826256 Cardiovascular NA NA Nephropathy NA diseases 48 APOE 6.82234 7.944106 6.992464 7.366049 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 49 APOH 5.148258 5.659615 5.339681 5.507452 Cardiovascular NA NA NA NA diseases 50 APOL1 6.493527 7.754781 6.732508 7.07018 Cardiovascular NA NA Nephropathy NA diseases 51 APOM 6.036542 6.722021 6.299858 6.546864 NA NA Atherosclerosis NA NA

52 APPL1 7.933185 9.195864 8.668863 9.063118 NA NA Atherosclerosis Nephropathy NA

53 AQP1 9.828492 11.09265 10.30861 10.71149 NA Retinopathy NA NA NA

54 AQP4 5.142832 5.909451 5.385153 5.646621 NA Retinopathy NA NA NA

55 AQP5 6.546644 7.413649 6.854054 7.150419 NA NA NA Nephropathy NA

56 AR 7.061269 7.986501 7.453403 7.756866 NA NA NA Nephropathy NA

57 ASPA 5.045429 6.921385 5.569651 6.044903 NA NA NA NA Neuropathy

58 ATF4 9.5032 10.46792 9.885864 10.17642 NA Retinopathy NA Nephropathy NA

59 ATM 7.016906 8.094209 7.528664 7.849022 Cardiovascular NA NA NA NA diseases 60 ATP2A2 10.6357 12.01618 10.97581 11.33413 NA NA NA NA Neuropathy

61 B2M 10.74911 11.86322 11.30637 11.59188 NA NA Atherosclerosis Nephropathy NA

62 BAAT 4.665405 5.279724 4.910537 5.079152 NA NA Atherosclerosis NA NA

63 BAMBI 7.226933 9.046215 7.930111 8.54943 NA NA NA Nephropathy NA

64 BASP1 7.05919 8.830531 8.117209 8.593636 NA NA NA Nephropathy NA

65 BCL2 6.45129 7.343438 6.773917 7.039268 NA NA NA Nephropathy NA

66 BDKRB1 5.675011 6.590076 5.916627 6.267268 NA NA NA NA Neuropathy

67 BDKRB2 6.102231 6.692235 6.201214 6.371081 NA NA NA NA Neuropathy

68 BDNF 5.63978 7.738851 5.859503 6.538127 NA Retinopathy NA NA Neuropathy

69 BMP2 6.275097 7.354564 6.555925 6.881351 NA NA Atherosclerosis NA NA

70 BMP4 6.051514 7.512207 6.586555 6.988975 NA NA NA Nephropathy NA

71 BNIP3 8.468241 9.58638 8.884794 9.255362 Cardiovascular NA NA NA NA diseases 72 C5 5.464573 6.45179 5.89241 6.175355 NA Retinopathy NA Nephropathy NA

73 CACNA1 6.76863 7.637522 7.191054 7.471873 NA NA NA NA Neuropathy H 74 CAPN10 6.540793 7.095241 6.7544 6.948998 NA NA Atherosclerosis NA NA

75 CAT 8.617701 9.988496 9.194808 9.612626 NA Retinopathy NA Nephropathy NA

76 CAV1 11.24402 12.26842 11.54005 11.89459 NA NA NA Nephropathy Neuropathy

77 CCK 5.396621 6.576198 5.81025 6.201026 NA NA NA Nephropathy Neuropathy

78 CCKAR 5.896904 6.857768 6.124384 6.443041 NA NA NA Nephropathy NA

79 CCL2 7.574293 11.65883 8.416783 9.956511 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

80 CCL20 5.066807 5.78918 5.337608 5.572498 NA NA NA Nephropathy NA

81 CCL5 6.074547 7.28698 6.433771 6.845999 NA NA NA Nephropathy NA

82 CCR1 5.988114 7.458854 6.353472 6.845143 NA NA NA Nephropathy NA

83 CCR2 4.935531 5.747344 5.269769 5.54083 NA NA Atherosclerosis Nephropathy NA

84 CCR5 5.855794 6.848804 6.216296 6.49582 NA NA Atherosclerosis Nephropathy NA

85 CD160 5.074398 6.063167 5.298098 5.602099 NA Retinopathy NA NA NA

86 CD163 5.744655 8.835627 6.666987 7.592918 NA Retinopathy Atherosclerosis NA Neuropathy

87 CD247 5.996979 7.150206 6.404556 6.763801 Cardiovascular NA NA NA NA diseases 88 CD2AP 7.691031 9.042803 8.19974 8.669433 NA NA NA Nephropathy NA

89 CD34 8.035264 9.966734 8.711457 9.23454 NA NA NA NA Neuropathy

90 CD36 8.515285 10.55034 9.085684 9.709918 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 91 CD38 6.552134 7.71896 7.00301 7.355473 NA NA NA Nephropathy NA

92 CD4 7.218195 8.203008 7.574259 7.938759 Cardiovascular NA Atherosclerosis NA NA diseases 93 CD40 6.16985 6.65564 6.382989 6.531693 Cardiovascular NA Atherosclerosis NA NA diseases 94 CD40LG 4.836804 5.561468 5.076122 5.272522 Cardiovascular NA NA Nephropathy NA diseases 95 CD47 8.190314 9.251669 8.552278 8.87366 NA NA NA Nephropathy NA

96 CD59 10.08329 11.31284 10.55538 10.93266 NA Retinopathy NA NA NA

97 CD63 10.21285 11.53369 10.43506 10.86313 NA NA NA Nephropathy NA

98 CD68 7.788306 9.251485 8.176193 8.633229 NA NA NA Nephropathy NA

99 CD69 4.279839 6.470357 4.839074 5.394016 NA NA NA Nephropathy NA

100 CD74 9.124373 11.32463 10.00978 10.7863 NA NA NA Nephropathy NA

101 CD80 5.427743 6.364483 5.734034 5.987244 NA NA NA Nephropathy NA

102 CD9 9.12638 10.3422 9.709933 10.08597 Cardiovascular NA NA NA NA diseases 103 CDC123 8.167042 9.049232 8.392784 8.696594 Cardiovascular NA NA NA NA diseases 104 CDH1 5.114463 5.424978 5.20115 5.311565 NA NA NA Nephropathy NA

105 CDH2 9.051165 10.33348 9.369089 9.831757 NA NA NA Nephropathy NA

106 CDK7 6.321487 6.984676 6.605268 6.820594 NA NA NA Nephropathy NA

107 CDKAL1 7.162834 8.162706 7.464212 7.772856 Cardiovascular NA NA Nephropathy NA diseases 108 CDKN1A 7.806198 10.8445 8.617257 9.684702 NA NA NA Nephropathy NA

109 CDKN2A 5.741103 6.806764 6.230619 6.521049 Cardiovascular NA NA NA NA diseases 110 CETP 5.120868 5.723985 5.297753 5.474061 Cardiovascular NA Atherosclerosis NA NA diseases 111 CHI3L1 5.436089 6.732332 5.63094 6.018453 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 112 CHIT1 5.603685 6.501024 5.884035 6.119596 NA NA NA Nephropathy NA

113 CHN2 7.288598 9.6218 7.694746 8.296838 NA Retinopathy NA Nephropathy NA

114 CHPT1 9.574088 10.83336 9.878015 10.26398 NA NA NA Nephropathy NA

115 CISH 7.337219 9.362219 7.912449 8.495466 NA NA NA Nephropathy NA

116 CITED2 8.396254 10.24698 8.812447 9.366977 NA NA Atherosclerosis NA NA

117 CLCN5 5.811062 7.159421 6.07594 6.503892 NA NA NA Nephropathy NA

118 CLEC11A 6.366512 7.093927 6.470896 6.683016 NA NA NA Nephropathy NA

119 CLOCK 7.78202 8.923144 8.183541 8.533991 Cardiovascular NA NA NA NA diseases 120 CMA1 5.194775 6.074458 5.528624 5.752269 NA NA NA Nephropathy NA

121 CMC4 7.276541 8.203513 7.430349 7.714911 NA NA NA Nephropathy NA

122 CNDP2 7.833785 8.511948 8.072396 8.274426 NA NA NA Nephropathy NA

123 CNR1 5.210584 6.341868 5.546049 5.921134 NA Retinopathy NA Nephropathy Neuropathy

124 CNR2 6.156955 7.02145 6.392942 6.677505 NA NA NA Nephropathy Neuropathy

125 CNTF 6.555511 8.017475 6.841085 7.308052 NA NA NA NA Neuropathy

126 COG2 7.039346 7.773804 7.303978 7.530077 NA NA Atherosclerosis NA NA

127 COL8A1 6.266075 7.789259 6.934573 7.373468 NA NA NA Nephropathy NA

128 COL8A2 6.917505 8.027502 7.301374 7.645057 NA NA NA Nephropathy NA

129 COLEC12 6.878018 8.733281 7.501591 8.062614 NA Retinopathy NA NA NA

130 COMT 8.411571 9.006478 8.585678 8.758389 Cardiovascular NA NA NA NA diseases 131 CPVL 6.555537 7.57809 6.877299 7.214894 NA NA NA Nephropathy NA

132 CRH 5.059056 5.893791 5.264645 5.576859 NA NA NA NA Neuropathy

133 CRK 8.51811 9.621937 8.701444 9.053162 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 134 CRP 5.367607 6.166815 5.614417 5.897373 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 135 CST3 10.51041 11.67887 10.95453 11.30992 Cardiovascular NA NA NA NA diseases 136 CTGF 9.809372 11.30783 10.2813 10.90757 NA Retinopathy NA Nephropathy NA

137 CTSH 7.358635 8.611642 7.624265 7.999067 NA Retinopathy NA NA NA

138 CTSS 5.369268 7.35559 6.235452 6.906432 Cardiovascular NA NA NA NA diseases 139 CUBN 5.969093 7.328501 6.625085 7.025971 NA NA NA Nephropathy NA

140 CX3CL1 8.069146 9.218166 8.408875 8.7227 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 141 CX3CR1 5.613868 7.560114 6.400971 7.06527 NA NA NA Nephropathy NA

142 CXCL10 5.63006 8.262213 6.12168 6.802583 NA NA NA Nephropathy Neuropathy

143 CXCL11 4.616158 5.594055 4.759141 5.057603 NA NA NA Nephropathy NA

144 CXCL12 8.203063 9.381125 8.505467 8.891656 NA NA NA Nephropathy NA

145 CXCL5 5.675 5.934246 5.734776 5.824701 NA NA Atherosclerosis Nephropathy NA

146 CXCL8 5.813947 8.055586 6.296084 7.011649 NA NA NA Nephropathy NA

147 CXCL9 5.545444 7.532967 5.894412 6.434498 NA NA NA Nephropathy NA

148 CYBA 6.490059 7.749787 7.078934 7.540343 NA NA Atherosclerosis Nephropathy NA

149 CYBB 6.969639 8.241901 7.313939 7.725903 NA Retinopathy NA NA NA

150 CYP1A1 5.532284 6.249141 5.799085 6.034913 Cardiovascular NA Atherosclerosis NA NA diseases 151 CYP24A1 4.491492 5.260633 4.692617 4.94606 NA NA NA Nephropathy NA

152 CYP2C19 4.405406 5.035405 4.629584 4.779969 NA Retinopathy NA NA NA

153 CYP2J2 7.518341 8.643779 7.893919 8.211453 Cardiovascular NA NA Nephropathy NA diseases 154 CYP7A1 4.554071 5.641796 4.760919 5.042515 Cardiovascular NA NA NA NA diseases 155 CYR61 8.299771 11.5036 9.415059 10.46579 NA Retinopathy NA NA NA

156 DCXR 8.877097 10.15623 9.251815 9.618415 NA NA NA Nephropathy NA

157 DDAH1 8.542948 10.52214 9.229823 9.872223 NA Retinopathy NA Nephropathy NA

158 DDIT3 7.213181 8.679441 7.665348 8.06992 Cardiovascular NA NA Nephropathy Neuropathy diseases 159 DES 10.98403 12.5974 11.65308 12.09159 NA NA NA Nephropathy NA

160 DGKH 6.589459 7.678563 7.167748 7.450532 NA NA NA Nephropathy NA

161 DHCR7 6.818867 7.837835 7.146436 7.443934 NA NA Atherosclerosis NA NA

162 DKK1 5.385517 8.470345 5.788328 6.673796 Cardiovascular Retinopathy NA Nephropathy NA diseases 163 DNMT1 7.316456 8.754243 7.805934 8.178904 NA NA NA Nephropathy NA

164 DPP4 6.112888 7.666473 6.658756 7.139467 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 165 EBF2 6.445166 7.464262 6.809441 7.093993 NA NA NA Nephropathy NA

166 EDN1 6.589415 7.961464 6.902269 7.422634 NA Retinopathy NA Nephropathy Neuropathy

167 EDNRA 7.529248 9.462025 8.317682 8.865425 NA NA NA Nephropathy NA

168 EGF 5.974802 7.093123 6.530314 6.8676 NA NA NA Nephropathy NA

169 EGFR 7.485519 8.384589 7.84067 8.064514 Cardiovascular NA NA Nephropathy NA diseases 170 EIF2AK3 6.989603 8.194954 7.45219 7.790766 NA NA NA Nephropathy NA

171 EIF4EBP 7.160472 8.180112 7.404098 7.725562 NA NA NA Nephropathy NA 1 172 ELMO1 6.621015 8.07229 7.06432 7.482338 NA NA NA Nephropathy NA

173 ELN 8.831014 10.39075 9.515897 9.954492 NA NA Atherosclerosis NA NA

174 ENG 8.217405 9.350213 8.616081 8.95935 Cardiovascular Retinopathy NA NA Neuropathy diseases 175 ENPP1 6.099137 7.229518 6.576203 6.879509 NA NA NA Nephropathy NA

176 ENPP2 6.682073 9.877825 7.821089 8.843749 NA NA NA NA Neuropathy

177 ENTPD1 7.448113 8.713415 7.794184 8.196913 NA NA Atherosclerosis Nephropathy NA

178 EPO 5.906644 6.792109 6.122183 6.406984 NA Retinopathy NA Nephropathy Neuropathy

179 EPOR 6.39324 7.05504 6.517362 6.719077 NA NA NA Nephropathy NA

180 ERAP2 5.319653 7.928992 5.806429 6.692918 NA Retinopathy NA NA NA

181 ERBB2 6.781918 7.682192 7.155169 7.398449 Cardiovascular NA NA NA Neuropathy diseases 182 ERBB3 5.453928 6.413595 5.795096 6.05159 NA Retinopathy NA NA NA

183 ERBB4 6.858716 7.527526 6.993083 7.243753 NA NA NA Nephropathy NA

184 ERCC1 7.762366 8.756647 7.921331 8.252188 NA Retinopathy NA Nephropathy NA

185 ERCC4 6.467161 7.478838 6.873585 7.182174 NA Retinopathy NA Nephropathy NA

186 ESM1 5.084155 6.455962 5.283606 5.682284 NA NA NA NA Neuropathy

187 ESR1 6.410772 7.547527 6.899647 7.243177 NA NA NA Nephropathy NA

188 EXOSC7 7.166604 7.776297 7.313148 7.504549 NA NA NA Nephropathy NA

189 EZR 7.837526 9.280243 8.322578 8.652848 NA NA NA Nephropathy NA

190 F11 5.570805 5.990883 5.699793 5.848154 NA NA NA Nephropathy NA

191 F2R 8.3866 9.571528 8.831484 9.198564 NA NA NA Nephropathy NA

192 F8 7.862281 8.773443 8.082847 8.365517 NA NA NA NA Neuropathy

193 FABP1 4.850708 5.140859 4.914277 5.007537 Cardiovascular NA NA Nephropathy NA diseases 194 FABP2 4.677046 5.542827 5.016206 5.264096 NA NA NA Nephropathy NA

195 FABP4 6.806065 10.90298 7.223664 8.528936 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 196 FABP5 5.5402 8.788959 6.818705 7.631083 Cardiovascular NA Atherosclerosis NA NA diseases 197 FADS1 7.623758 9.06202 7.991984 8.444187 Cardiovascular NA NA NA NA diseases 198 FADS2 8.033145 10.04433 8.470959 9.053409 Cardiovascular NA NA NA NA diseases 199 FASN 6.669667 8.256852 7.13018 7.67413 NA NA NA Nephropathy NA

200 FFAR2 5.272936 6.236396 5.642121 5.916537 Cardiovascular NA NA NA NA diseases 201 FGF21 5.591773 6.18234 5.799444 6.001577 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 202 FGF23 6.262327 7.027183 6.47439 6.715775 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 203 FGFR1 8.579711 9.73853 8.810009 9.179101 NA NA Atherosclerosis NA NA

204 FKBP10 7.698387 9.071277 8.065078 8.52456 Cardiovascular NA NA NA NA diseases 205 FKBP2 7.575912 8.487829 7.901932 8.20188 NA NA Atherosclerosis NA NA

206 FKBP4 7.639128 9.217513 7.997333 8.488151 Cardiovascular NA NA NA NA diseases 207 FKBP8 7.745358 8.618019 7.95513 8.228814 Cardiovascular NA NA NA NA diseases 208 FMO3 5.733095 7.446242 6.559174 7.112993 NA NA Atherosclerosis NA NA

209 FMOD 8.461895 9.975753 8.871058 9.521716 NA NA Atherosclerosis NA NA

210 FN3K 6.548133 7.889014 7.153094 7.535959 NA NA NA Nephropathy NA

211 FOLH1 4.412005 4.962348 4.533042 4.745627 NA NA NA NA Neuropathy

212 FOS 7.084742 10.86231 9.232856 10.44224 NA NA NA Nephropathy NA

213 FOXA2 5.959912 6.708965 6.216764 6.472612 NA NA Atherosclerosis NA NA

214 FOXO1 8.007365 8.709763 8.300433 8.485347 NA NA Atherosclerosis NA NA

215 FOXO4 7.026087 8.270845 7.362116 7.720345 NA NA NA Nephropathy NA

216 FPR1 5.304373 7.012034 5.745934 6.297623 NA NA Atherosclerosis NA NA

217 FTO 9.144293 10.05573 9.392345 9.663343 Cardiovascular NA NA Nephropathy NA diseases 218 G6PD 7.101665 8.113215 7.333084 7.685282 Cardiovascular NA NA Nephropathy Neuropathy diseases 219 GAP43 6.096658 8.508018 6.650997 7.466972 NA NA NA NA Neuropathy

220 GAPDH 12.66714 13.23582 12.85638 13.04079 NA Retinopathy NA NA Neuropathy

221 GAS1 6.017066 7.138863 6.469274 6.804804 NA NA NA Nephropathy NA

222 GAS6 8.946244 10.0802 9.473081 9.869139 NA NA NA Nephropathy NA

223 GCG 4.688757 5.220822 4.911022 5.105348 NA NA NA Nephropathy NA

224 GCK 6.242865 7.105976 6.519672 6.785234 NA NA NA Nephropathy Neuropathy

225 GCKR 5.447536 6.206624 5.593517 5.83639 Cardiovascular NA NA NA NA diseases 226 GDF15 6.021916 6.72578 6.233434 6.449566 Cardiovascular NA NA Nephropathy NA diseases 227 GDNF 5.507757 6.143465 5.729931 5.947413 NA Retinopathy NA NA Neuropathy

228 GFAP 6.446908 7.368245 6.726549 7.028707 NA NA NA NA Neuropathy

229 GFPT1 8.280443 9.3255 8.683295 9.060543 NA NA NA Nephropathy NA

230 GFPT2 6.520409 8.881128 6.793624 7.562764 NA NA NA Nephropathy NA

231 GHR 7.362151 8.737599 7.973147 8.488294 NA NA NA Nephropathy NA

232 GHSR 5.75609 6.478818 6.030782 6.274428 NA NA NA Nephropathy NA

233 GIP 5.211916 5.688097 5.384104 5.551811 Cardiovascular NA Atherosclerosis NA Neuropathy diseases 234 GIPR 6.45329 6.842407 6.52969 6.680858 NA Retinopathy NA NA Neuropathy

235 GK 6.382852 7.595754 6.693805 7.000885 Cardiovascular NA NA NA NA diseases 236 GLO1 9.252852 10.4554 9.700077 10.01044 NA NA Atherosclerosis Nephropathy Neuropathy

237 GLP1R 6.306829 7.374238 6.713771 7.058045 Cardiovascular NA NA NA Neuropathy diseases 238 GLUL 7.903374 9.407952 8.495384 8.961662 Cardiovascular NA NA NA NA diseases 239 GNB3 6.864871 7.488117 7.053441 7.252561 NA NA NA Nephropathy NA

240 GPC5 5.301506 6.69564 5.806723 6.218352 NA NA NA Nephropathy NA

241 GPX1 7.677302 8.644341 8.056603 8.372455 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 242 GRB2 7.304332 8.502239 7.740525 8.104754 NA Retinopathy NA NA NA

243 GREM1 5.767065 6.648732 6.148418 6.409695 NA NA NA Nephropathy NA

244 GSTM1 7.573915 9.113352 8.124713 8.594809 NA Retinopathy Atherosclerosis Nephropathy NA

245 GSTT1 5.600601 9.955816 7.342195 9.063413 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 246 GYS1 8.792804 9.75694 9.1377 9.438961 Cardiovascular NA NA NA NA diseases 247 HBG2 5.786605 7.116018 6.249886 6.638205 NA Retinopathy NA NA NA

248 HCN2 6.360365 7.634867 6.694297 7.110686 NA NA NA NA Neuropathy

249 HDAC4 7.184177 7.725932 7.367371 7.567371 NA NA NA Nephropathy NA

250 HDAC9 7.113096 8.74639 7.473815 8.045633 NA NA Atherosclerosis NA NA

251 HFE 5.898623 6.64822 6.074791 6.384245 NA Retinopathy NA Nephropathy NA

252 HGF 5.922852 7.871408 6.662506 7.333431 NA NA Atherosclerosis Nephropathy Neuropathy

253 HHEX 5.864139 6.886371 6.162815 6.425611 Cardiovascular NA NA Nephropathy NA diseases

254 HIF1A 9.754156 11.05306 9.937383 10.34385 Cardiovascular NA NA Nephropathy NA diseases 255 HLA-A 9.16629 10.91789 9.967106 10.50122 NA NA NA Nephropathy NA

256 HLA- 6.655529 8.911651 7.401959 8.177573 NA NA NA Nephropathy NA DQA1 257 HMGA2 5.330257 6.256972 5.625912 5.866146 NA NA NA Nephropathy NA

258 HMGB1 8.050843 8.959048 8.416474 8.703701 Cardiovascular Retinopathy NA Nephropathy NA diseases 259 HMGCS2 5.486675 7.660812 6.188097 6.920755 NA NA NA Nephropathy NA

260 HMOX1 6.531726 8.079029 6.784108 7.285176 NA NA NA Nephropathy NA

261 HNF1A 6.371958 7.64323 6.764935 7.230323 NA NA NA Nephropathy NA

262 HNF1B 5.878459 7.30658 6.374198 6.798445 Cardiovascular NA NA NA NA diseases 263 HNF4A 6.350388 7.343051 6.609722 6.94292 Cardiovascular NA NA NA NA diseases 264 HP 5.268323 6.141566 5.596732 5.948911 Cardiovascular NA Atherosclerosis NA NA diseases 265 HPSE 5.431158 6.355927 5.798779 6.051084 NA NA NA Nephropathy NA

266 HRH1 6.505979 7.604822 6.875326 7.22887 NA NA NA NA Neuropathy

267 HRH2 6.556852 7.588387 6.969001 7.292189 NA NA NA NA Neuropathy

268 HSPA1A 10.5249 12.52251 11.13282 11.74057 NA NA NA Nephropathy NA

269 HSPA1B 9.027648 11.4601 9.558532 10.46452 NA NA NA Nephropathy NA

270 HSPA5 9.500304 11.53953 10.46513 11.0742 NA NA NA NA Neuropathy

271 HSPB1 12.30081 13.56143 12.59959 12.99471 NA NA NA Nephropathy NA

272 HSPG2 7.953327 9.51949 8.417418 8.841293 NA NA NA Nephropathy NA

273 HTR2A 5.809253 6.727665 6.083649 6.370739 NA NA NA Nephropathy NA

274 HYOU1 7.96281 9.473599 8.357973 8.879655 NA NA NA Nephropathy Neuropathy

275 ICAM1 6.878025 8.517584 7.235573 7.799159 NA NA Atherosclerosis Nephropathy NA

276 ID1 7.544297 9.646048 8.48899 9.07251 NA NA NA Nephropathy NA

277 IFNG 5.261524 6.245627 5.407867 5.780177 NA NA NA Nephropathy Neuropathy

278 IGF1 6.488309 8.875059 6.839625 7.532228 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 279 IGF1R 8.433326 9.47775 8.813009 9.165479 NA Retinopathy NA NA NA

280 IGFBP1 6.304612 7.141518 6.519272 6.769635 NA NA NA Nephropathy NA

281 IGFBP3 7.293201 9.511866 8.025665 8.663183 NA NA NA Nephropathy NA

282 IGFBP5 9.74537 11.27192 10.12078 10.67784 NA NA NA NA Neuropathy

283 IGFBP7 12.11282 12.87818 12.36201 12.62996 NA NA NA Nephropathy NA

284 IL10 5.226289 6.128821 5.462716 5.747979 NA NA NA Nephropathy Neuropathy

285 IL17A 5.867264 7.112755 6.209939 6.542895 NA Retinopathy NA Nephropathy NA

286 IL18 4.684884 5.767921 4.910396 5.211824 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 287 IL1B 5.782303 7.244688 6.087164 6.543022 Cardiovascular Retinopathy NA Nephropathy NA diseases 288 IL1RN 5.299532 6.898317 5.781166 6.328438 NA NA NA Nephropathy NA

289 IL4 4.570018 4.919371 4.673058 4.802492 NA NA NA NA Neuropathy

290 IL6 5.205016 8.244374 5.855075 6.982486 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

291 ILK 10.44604 11.14965 10.65626 10.9232 NA NA NA Nephropathy NA

292 INS 6.539851 7.390848 6.745051 6.991203 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 293 IRAK1 7.553687 8.588919 7.917585 8.263787 NA NA NA NA Neuropathy

294 IRAK4 6.884542 7.700945 7.24835 7.499548 NA NA Atherosclerosis NA NA

295 IRS1 6.8176 8.227682 7.293454 7.688265 NA Retinopathy NA NA NA

296 IRS2 7.827959 9.589333 8.436099 8.96849 NA NA Atherosclerosis Nephropathy Neuropathy

297 ITGA2 5.083971 8.265462 5.915174 6.685595 NA Retinopathy NA NA NA

298 ITGAM 6.310344 7.844609 6.711464 7.206747 NA Retinopathy NA Nephropathy NA

299 ITGB3 6.587055 8.214215 6.993619 7.476355 NA Retinopathy NA NA NA

300 JAK2 8.026932 9.66454 8.633667 9.041794 NA NA NA Nephropathy NA

301 KCNQ1 6.56352 7.513271 6.769826 7.107815 NA NA NA Nephropathy NA

302 KDM1A 7.412899 8.125789 7.585032 7.822726 NA Retinopathy NA NA NA

303 KL 5.544915 6.169431 5.769172 5.991847 NA NA NA Nephropathy NA

304 KLF10 8.462582 10.2 8.970256 9.449337 NA NA NA Nephropathy NA

305 KLF6 7.651037 9.263442 8.188418 8.713661 NA NA NA Nephropathy NA

306 L1CAM 5.927732 6.914872 6.356367 6.629411 NA Retinopathy NA NA NA

307 LAMC1 8.932327 9.590248 9.114053 9.348538 NA NA NA Nephropathy NA

308 LAP3 8.222667 9.230357 8.555272 8.792146 NA NA NA Nephropathy NA

309 LDLR 7.331782 9.367511 7.713309 8.403922 Cardiovascular NA Atherosclerosis NA NA diseases 310 LEP 5.836701 6.83071 6.182378 6.480611 NA NA Atherosclerosis NA Neuropathy

311 LIMK2 7.077591 8.049283 7.348949 7.662896 NA NA NA Nephropathy NA

312 LMNA 8.521752 9.451955 8.898087 9.230015 NA NA NA Nephropathy NA

313 LPA 5.261752 5.620352 5.346386 5.47071 Cardiovascular NA Atherosclerosis NA NA diseases 314 LPL 8.049092 10.25247 8.546003 9.215463 Cardiovascular NA Atherosclerosis Nephropathy Neuropathy diseases 315 LPO 5.743421 6.657205 6.142302 6.422735 NA Retinopathy NA NA NA

316 LRP2 4.882926 5.761062 5.327866 5.588811 NA NA NA Nephropathy NA

317 LTA 6.159635 7.112274 6.318838 6.582051 NA NA NA Nephropathy NA

318 LTB4R2 6.004275 6.711996 6.191884 6.427533 NA Retinopathy NA NA NA

319 MAFB 7.241487 8.479376 7.770269 8.202913 Cardiovascular NA Atherosclerosis NA NA diseases 320 MALT1 6.638242 7.45609 6.936889 7.23103 NA NA NA Nephropathy NA

321 MAP3K5 7.832747 9.163745 8.233022 8.668154 Cardiovascular NA NA Nephropathy NA diseases 322 MAPK1 8.4381 9.222673 8.655683 8.953061 NA NA NA Nephropathy Neuropathy

323 MAPK14 7.801032 8.740957 8.109768 8.440763 NA NA NA Nephropathy NA

324 MAPK7 7.387962 8.408138 7.711075 8.057565 NA Retinopathy NA NA NA

325 MBL2 5.137707 5.96847 5.30077 5.541245 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 326 MBP 6.682597 7.999701 7.040187 7.482027 NA NA NA NA Neuropathy

327 MC4R 5.388331 6.183439 5.685621 5.928734 Cardiovascular NA NA Nephropathy NA diseases 328 MCAM 9.381291 10.66458 9.788154 10.22315 NA NA NA Nephropathy NA

329 MEP1B 4.978111 5.876135 5.250758 5.510846 NA NA NA Nephropathy NA

330 MIF 8.255214 9.627999 8.934513 9.388077 NA NA Atherosclerosis Nephropathy Neuropathy

331 MME 5.913618 7.128519 6.356538 6.756119 NA NA NA NA Neuropathy

332 MMP14 6.92709 8.02415 7.320275 7.62861 NA NA NA Nephropathy NA

333 MMP16 5.796085 7.173498 6.230593 6.752598 NA NA NA Nephropathy NA

334 MMP2 8.599919 10.61281 9.108224 9.686513 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 335 MMP24 5.70434 6.498729 5.9903 6.207104 NA NA NA Nephropathy NA

336 MMP9 6.238289 7.122005 6.615636 6.906427 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 337 MOK 6.228185 7.092778 6.553438 6.827893 NA NA Atherosclerosis Nephropathy NA

338 MPO 5.54351 6.028854 5.641474 5.788155 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 339 MRPL28 8.592732 9.119098 8.783566 8.938974 NA Retinopathy NA NA NA

340 MSH2 5.546143 7.060723 6.207444 6.613889 Cardiovascular NA NA NA NA diseases 341 MTHFR 7.020348 8.401443 7.305767 7.771011 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

342 MTOR 8.076235 8.697092 8.182473 8.413328 NA NA NA Nephropathy NA

343 MYD88 7.968233 9.428834 8.510099 9.051084 NA NA NA Nephropathy NA

344 MYH9 9.460592 11.74144 10.11983 10.81555 NA NA NA Nephropathy NA

345 MYO5C 5.508918 6.723678 5.891476 6.292575 NA Retinopathy NA NA NA

346 NAGLU 6.509959 8.053695 7.306964 7.679093 Cardiovascular Retinopathy NA NA NA diseases 347 NAMPT 8.584577 10.50777 9.240594 9.792351 Cardiovascular NA NA NA NA diseases 348 NCALD 6.525244 7.500749 6.772869 7.089635 NA NA NA Nephropathy NA

349 NCF1 5.46066 7.749545 6.210836 6.893283 NA NA NA Nephropathy NA

350 NCF2 6.055981 7.186942 6.425466 6.738087 NA NA NA Nephropathy NA

351 NDUFS3 9.11101 10.15557 9.458246 9.79193 NA NA NA Nephropathy NA

352 NEDD4L 7.167057 8.145255 7.436052 7.732576 NA NA NA Nephropathy NA

353 NFE2 5.57987 6.423276 5.738312 5.954034 NA NA NA Nephropathy NA

354 NFE2L2 9.187849 10.24224 9.590993 9.955611 NA Retinopathy NA Nephropathy Neuropathy

355 NFKBIA 8.953896 9.878558 9.289696 9.585844 NA NA NA Nephropathy NA

356 NGB 6.166639 7.088568 6.522541 6.758916 NA Retinopathy NA NA NA

357 NGF 6.746659 7.395165 6.849611 7.0298 NA NA NA Nephropathy Neuropathy

358 NGFR 6.65645 7.798504 6.893776 7.231599 NA NA NA NA Neuropathy

359 NLRP3 5.596931 6.756723 6.082699 6.400076 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 360 NME2 7.116694 8.743771 7.614621 8.082654 NA Retinopathy NA NA NA

361 NOD2 5.978384 6.716315 6.135434 6.35217 NA NA NA Nephropathy NA

362 NOS1 6.011084 7.198517 6.375758 6.714959 NA Retinopathy NA Nephropathy Neuropathy

363 NOS2 5.988554 6.832439 6.214298 6.524689 NA Retinopathy NA Nephropathy NA

364 NOS3 6.313726 7.334352 6.58647 6.845865 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 365 NOV 8.512964 9.841195 9.010886 9.487329 NA NA NA Nephropathy NA

366 NOX1 5.128638 5.614168 5.266766 5.427902 NA NA NA Nephropathy NA

367 NOX3 5.346861 6.124193 5.505487 5.740535 NA NA NA Nephropathy NA

368 NOX4 6.747167 9.20386 7.256268 8.047877 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 369 NPHS1 5.386828 5.999951 5.57433 5.760017 NA NA NA Nephropathy NA

370 NPPA 6.758068 9.605039 7.886338 9.003969 Cardiovascular NA NA NA NA diseases 371 NPY 6.012587 7.14415 6.365324 6.685958 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

372 NPY2R 5.900232 6.792742 6.264811 6.568309 Cardiovascular NA NA NA NA diseases 373 NPY5R 5.329137 6.27986 5.692519 5.990274 Cardiovascular NA NA NA NA diseases 374 NQO1 6.68709 8.42281 6.948348 7.424744 Cardiovascular NA Atherosclerosis NA NA diseases 375 NR1H3 6.594904 7.467539 6.881769 7.148595 NA NA NA Nephropathy NA

376 NR3C2 7.157295 8.219312 7.562017 7.914602 Cardiovascular NA NA NA NA diseases 377 NRF1 7.099777 7.547937 7.274822 7.400165 NA NA NA NA Neuropathy

378 NSA2 9.313168 10.89583 9.586411 10.03171 NA NA NA Nephropathy NA

379 NTF3 6.463296 7.31361 6.722635 7.003353 NA NA NA NA Neuropathy

380 NTS 4.697074 5.396879 4.888147 5.128457 Cardiovascular NA NA NA NA diseases 381 NUCB2 7.466562 8.488328 7.968669 8.305653 Cardiovascular Retinopathy NA NA NA diseases 382 ONECUT 6.282855 7.021843 6.476328 6.708772 NA NA NA Nephropathy NA 1 383 OSM 6.206396 6.859294 6.438625 6.679494 NA NA NA Nephropathy NA

384 OXT 6.663125 7.717536 7.001778 7.324224 Cardiovascular NA NA NA NA diseases 385 P2RX2 5.941896 6.627342 6.083582 6.279665 NA NA NA NA Neuropathy

386 P2RX3 5.631903 6.606949 5.830304 6.130437 NA NA NA NA Neuropathy

387 P2RY1 6.023067 6.610562 6.217582 6.40658 NA NA NA NA Neuropathy

388 P2RY2 6.929094 8.231434 7.216588 7.604412 NA NA NA NA Neuropathy

389 PAK6 5.9069 6.644816 6.114878 6.38187 NA NA NA NA Neuropathy

390 PARL 7.990959 8.714605 8.227608 8.484793 Cardiovascular NA NA Nephropathy NA diseases 391 PARP1 8.372513 9.127616 8.588607 8.844988 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 392 PC 6.199155 6.840978 6.387223 6.585257 NA NA NA Nephropathy NA

393 PDE5A 6.277798 8.232567 7.292011 7.955523 NA NA NA Nephropathy Neuropathy

394 PDGFA 7.683483 9.386422 8.352809 8.940193 NA NA NA Nephropathy NA

395 PDGFB 6.649519 7.582296 6.900134 7.136191 NA NA NA Nephropathy NA

396 PDGFD 7.174178 9.171726 7.839978 8.508731 NA NA Atherosclerosis NA NA

397 PDGFRB 9.257911 10.31257 9.711574 9.988134 NA NA NA Nephropathy NA

398 PDHX 8.967687 9.961345 9.286642 9.592409 NA Retinopathy NA NA NA

399 PDK1 7.525582 8.351016 7.787602 8.079744 NA NA NA Nephropathy NA

400 PDPK1 7.3287 8.400312 7.840974 8.148375 NA NA NA Nephropathy NA

401 PEBP1 9.421831 10.74268 9.832096 10.23981 NA NA NA Nephropathy NA

402 PECAM1 8.067528 9.990225 8.679206 9.340907 NA NA NA NA Neuropathy

403 PFKFB2 6.89129 8.431719 7.54449 8.031165 NA NA NA Nephropathy NA

404 PGF 6.803799 7.51038 7.171888 7.396557 Cardiovascular NA NA NA NA diseases 405 PHACTR1 7.055574 8.175544 7.505429 7.84263 Cardiovascular NA NA NA NA diseases 406 PICK1 7.203827 8.037105 7.409628 7.667612 NA NA NA Nephropathy NA

407 PIGF 6.244102 7.569069 6.850323 7.273685 NA Retinopathy NA NA NA

408 PIK3CA 7.355093 8.101472 7.629036 7.893723 NA NA NA Nephropathy NA

409 PIP 5.596932 6.668359 5.976654 6.29137 NA NA NA Nephropathy NA

410 PLA2G2A 6.542118 9.271042 7.121328 8.146168 NA NA Atherosclerosis NA NA

411 PLIN1 6.350877 7.526231 6.718139 7.095553 Cardiovascular NA NA NA NA diseases 412 PLIN2 7.665013 10.24204 8.031039 8.717838 Cardiovascular NA NA NA NA diseases 413 PLN 11.20654 12.15542 11.69283 11.99137 Cardiovascular NA NA NA NA diseases 414 PLTP 8.049556 10.14175 8.549403 9.167864 NA NA Atherosclerosis NA NA

415 PLXDC1 6.989346 8.490959 7.455231 7.953183 NA Retinopathy NA NA NA

416 PMP22 10.60399 11.42031 10.85535 11.11503 NA NA NA NA Neuropathy

417 PNPLA3 5.201373 5.763969 5.375317 5.567941 Cardiovascular NA NA NA NA diseases 418 POLR2D 6.936551 7.748457 7.231444 7.459775 NA Retinopathy NA NA NA

419 POMC 6.220314 7.257591 6.396487 6.662513 Cardiovascular NA NA NA Neuropathy diseases 420 PON1 4.964724 5.828552 5.17264 5.432321 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 421 PON2 8.338284 9.578218 8.73081 9.098609 NA NA Atherosclerosis Nephropathy NA

422 PON3 5.790915 7.077532 6.176898 6.569089 Cardiovascular NA Atherosclerosis NA NA diseases 423 POSTN 9.044885 12.25396 9.976637 11.00321 NA Retinopathy NA Nephropathy NA

424 PPARA 7.377594 8.217557 7.672261 7.93607 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 425 PPARG 6.817859 7.45004 6.978532 7.174922 NA Retinopathy Atherosclerosis Nephropathy NA

426 PPARGC1 7.606237 8.922936 8.103848 8.459202 Cardiovascular Retinopathy NA Nephropathy Neuropathy A diseases 427 PPIA 10.95718 12.35534 11.20829 11.65533 Cardiovascular NA NA Nephropathy NA diseases 428 PPY 5.003587 5.709134 5.209317 5.435396 NA NA NA NA Neuropathy

429 PRCP 8.289787 9.460537 8.629868 8.963825 Cardiovascular NA Atherosclerosis Nephropathy NA diseases

430 PRDX1 9.879606 10.83128 10.19369 10.48285 Cardiovascular NA NA NA NA diseases 431 PRDX2 6.984308 7.952947 7.340988 7.636591 Cardiovascular NA NA NA NA diseases 432 PRDX4 7.224047 8.827282 7.729096 8.188431 Cardiovascular NA NA NA NA diseases 433 PRDX6 9.874673 10.90426 10.27344 10.62406 Cardiovascular NA NA NA NA diseases 434 PRKAA1 7.494666 7.993722 7.581721 7.744959 NA NA NA Nephropathy NA

435 PRKCB 6.16034 6.92009 6.388528 6.618331 NA NA NA Nephropathy Neuropathy

436 PRKCE 6.575561 7.333812 6.804135 7.023275 NA NA NA Nephropathy NA

437 PRKG1 7.82725 9.403546 8.506218 8.969578 NA NA NA NA Neuropathy

438 PRMT2 7.641392 8.571978 7.907135 8.224902 NA NA Atherosclerosis NA NA

439 PROC 5.792534 6.458844 5.973676 6.198112 NA NA NA Nephropathy NA

440 PROM1 5.716503 8.011401 6.222943 6.864626 NA NA NA NA Neuropathy

441 PSIP1 7.163739 8.419213 7.74947 8.157998 NA Retinopathy NA NA NA

442 PSMA6 9.142985 10.43958 9.481764 9.871709 Cardiovascular NA NA Nephropathy NA diseases 443 PSMD9 7.352616 8.335693 7.61676 7.896407 NA Retinopathy NA Nephropathy Neuropathy

444 PTEN 8.997674 9.672029 9.214432 9.40848 NA NA NA Nephropathy Neuropathy

445 PTGDS 8.795427 9.963955 9.060384 9.481389 NA NA Atherosclerosis Nephropathy NA

446 PTGER1 6.437115 7.254936 6.756545 6.974659 NA NA NA Nephropathy NA

447 PTGER4 6.836413 7.600212 7.117894 7.346709 NA NA NA Nephropathy NA

448 PTGES 6.481688 7.011871 6.668699 6.85075 NA NA NA Nephropathy NA

449 PTGS2 5.307121 8.512675 6.030859 7.087919 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 450 PTH 4.208897 5.01212 4.389995 4.665 Cardiovascular NA NA Nephropathy NA diseases 451 PTH1R 6.963583 8.163206 7.331024 7.69061 NA NA NA Nephropathy NA

452 PTPN1 8.21563 10.30862 8.551428 9.214794 Cardiovascular NA NA Nephropathy NA diseases 453 PTX3 4.937749 8.010968 5.096793 6.001439 NA Retinopathy Atherosclerosis Nephropathy NA

454 RAF1 9.26381 10.07719 9.544201 9.841687 NA Retinopathy NA Nephropathy NA

455 RARRES2 7.300582 8.642763 7.926743 8.284613 Cardiovascular NA NA NA NA diseases 456 RBP1 6.542933 7.67672 7.070147 7.380028 NA Retinopathy NA NA NA

457 RBP4 5.523005 7.074075 6.0397 6.558914 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 458 RCAN1 8.075839 10.23463 8.448704 9.052767 NA NA NA Nephropathy NA

459 REG1A 4.973186 5.925009 5.344227 5.567995 NA NA NA Nephropathy NA

460 RELA 8.180513 9.619386 8.703354 9.079994 NA Retinopathy NA Nephropathy NA

461 REN 5.515853 6.253115 5.767741 5.98273 Cardiovascular NA Atherosclerosis NA NA diseases 462 RETN 6.781408 7.670456 7.033066 7.382751 Cardiovascular NA Atherosclerosis NA NA diseases 463 RGN 6.386971 8.132891 7.103895 7.707317 NA NA NA Nephropathy NA

464 RHO 5.6882 6.453434 5.906023 6.156958 NA Retinopathy NA NA NA

465 RHOA 11.21047 12.03718 11.57662 11.8352 NA NA NA NA Neuropathy

466 RHOD 7.699821 9.156258 7.928126 8.353704 NA NA NA Nephropathy NA

467 RNLS 6.840727 7.764804 7.245903 7.549065 Cardiovascular NA NA NA NA diseases 468 ROCK1 8.948826 10.2749 9.460301 9.844449 NA NA NA Nephropathy NA

469 ROCK2 8.77382 9.951426 9.079687 9.464018 NA NA Atherosclerosis NA NA

470 RPS12 8.91784 10.84143 9.62699 10.14544 NA NA NA Nephropathy NA

471 RPS6 11.15714 12.25997 11.47694 11.82911 NA NA NA Nephropathy NA

472 RPS6KA6 5.104013 6.250664 5.392593 5.746623 NA NA NA NA Neuropathy

473 RREB1 7.598033 8.262145 7.950942 8.131356 NA NA NA Nephropathy NA

474 RTN1 6.194865 8.330492 7.010716 7.684737 NA NA NA Nephropathy NA

475 S100A12 5.295801 7.736384 5.724092 6.396454 Cardiovascular Retinopathy NA NA NA diseases 476 SARDH 5.733961 6.449906 5.966734 6.154357 NA Retinopathy NA NA NA

477 SCARB1 6.643025 7.505726 6.918748 7.16241 NA NA Atherosclerosis NA NA

478 SELE 5.223265 7.677776 5.62762 6.442992 NA NA NA Nephropathy NA

479 SEMA3A 5.591481 7.156025 5.9862 6.524701 NA NA NA Nephropathy NA

480 SERPINB 4.674381 5.381674 4.846243 5.02898 NA NA NA Nephropathy NA 7 481 SERPINE 6.417468 12.55393 7.795899 9.749766 NA NA NA Nephropathy NA 1 482 SERPINF 7.859586 11.10596 9.010786 9.809494 NA Retinopathy NA Nephropathy Neuropathy 1 483 SERPINF 5.949484 6.887901 6.245108 6.534313 NA NA NA Nephropathy NA 2 484 SFI1 6.734018 7.255304 6.91687 7.094145 NA NA NA Nephropathy NA

485 SGK1 6.200588 8.734148 7.238949 8.107482 NA NA NA Nephropathy NA

486 SGK2 6.161067 7.227634 6.519186 6.820538 NA NA NA Nephropathy NA

487 SGK3 6.839093 7.848991 7.23577 7.538115 NA NA NA Nephropathy NA

488 SHBG 5.827142 6.711975 6.065146 6.34296 Cardiovascular NA NA NA NA diseases 489 SIGLEC1 6.330419 7.5156 6.62224 6.954383 NA NA NA Nephropathy NA

490 SIRT1 8.085468 8.606627 8.230704 8.401007 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 491 SIRT6 7.282979 7.978101 7.463226 7.693123 NA NA NA Nephropathy NA

492 SLC12A3 6.26152 7.00974 6.450002 6.728268 NA NA NA Nephropathy NA

493 SLC22A6 6.091811 6.955192 6.15358 6.410642 NA NA NA Nephropathy NA

494 SLC2A1 7.052601 8.656877 7.625447 8.173515 Cardiovascular NA NA Nephropathy NA diseases 495 SLC2A2 4.578107 5.75718 5.10855 5.510203 NA NA NA Nephropathy NA

496 SLC2A3 7.302813 8.757289 7.64147 8.209663 NA NA NA NA Neuropathy

497 SLC2A4 6.41431 8.44261 7.469713 8.054661 Cardiovascular NA NA Nephropathy Neuropathy diseases 498 SLC30A10 5.415256 6.484365 5.725027 6.04696 NA NA NA NA Neuropathy

499 SLC5A2 6.722961 7.762222 7.049255 7.40282 Cardiovascular NA NA NA NA diseases 500 SLC9A1 7.663016 8.689442 7.965418 8.296043 NA NA NA Nephropathy NA

501 SMAD1 6.911886 7.898292 7.234623 7.540525 NA NA NA Nephropathy NA

502 SMAD7 7.552446 8.823526 7.783127 8.262748 NA NA NA Nephropathy NA

503 SMG1 8.155932 9.366277 8.500769 8.958793 NA Retinopathy NA NA NA

504 SMPD1 7.607968 8.471873 7.899744 8.193444 NA Retinopathy NA NA NA

505 SOCS1 6.728089 8.043009 7.065339 7.595982 NA NA NA Nephropathy NA

506 SOCS2 6.58799 7.376543 6.815301 7.068667 NA NA NA Nephropathy NA

507 SOCS3 5.521045 9.334959 6.380837 7.596411 NA Retinopathy NA Nephropathy NA

508 SOD1 10.0024 11.03133 10.27147 10.6451 NA Retinopathy NA Nephropathy NA

509 SOD2 7.031029 8.242681 7.478624 7.796873 NA Retinopathy NA NA Neuropathy

510 SORBS2 10.1655 11.83598 10.71716 11.26571 NA NA NA Nephropathy NA

511 SOX9 6.758499 7.501215 7.028435 7.25452 NA NA NA Nephropathy NA

512 SPARC 11.64856 12.66645 11.97969 12.33639 NA Retinopathy NA Nephropathy NA

513 SPON2 6.612455 7.423443 6.884766 7.198862 NA NA NA Nephropathy NA

514 SPP1 6.446144 9.887088 6.975898 8.189771 Cardiovascular Retinopathy NA Nephropathy NA diseases 515 SRC 6.885043 7.450624 7.032613 7.232882 NA NA NA Nephropathy NA

516 SREBF1 6.61669 7.827063 7.049842 7.407734 NA NA NA Nephropathy Neuropathy

517 SRGN 8.68821 9.768809 8.959464 9.335842 NA Retinopathy NA NA NA

518 SST 5.559034 6.227901 5.817127 6.016395 NA Retinopathy NA Nephropathy NA

519 STAT1 8.423728 9.641606 8.761107 9.12573 NA NA NA Nephropathy NA

520 STAT3 9.911194 10.94603 10.14057 10.51456 NA Retinopathy NA Nephropathy NA

521 STAT5A 7.134573 7.656775 7.283218 7.43711 NA NA NA Nephropathy NA

522 STEAP4 7.186355 8.779993 7.479669 7.926161 NA NA Atherosclerosis NA NA

523 STK11 6.86377 7.290906 7.027665 7.172011 NA NA NA Nephropathy NA

524 SUMO4 7.623121 8.367445 7.806627 8.034582 Cardiovascular NA NA Nephropathy NA diseases 525 TACR1 5.355361 6.063086 5.513738 5.694435 Cardiovascular NA NA NA NA diseases 526 TCF7L2 7.340328 8.454405 7.570491 7.900077 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 527 TF 5.635752 6.33264 5.929094 6.142253 NA NA NA Nephropathy NA

528 TFAM 6.450563 7.558806 6.844487 7.225329 NA NA NA NA Neuropathy

529 TGFB1 6.550993 7.932321 6.921514 7.340837 Cardiovascular NA NA Nephropathy NA diseases 530 TGFBR1 7.005496 7.934662 7.349848 7.653294 NA NA NA Nephropathy NA

531 TH 5.834906 6.488868 6.051749 6.240562 NA Retinopathy NA NA Neuropathy

532 THBD 7.647401 9.230685 8.102379 8.579093 NA NA NA Nephropathy NA

533 THBS1 7.779252 10.46308 8.400069 9.129587 NA Retinopathy NA Nephropathy NA

534 THBS2 8.297294 10.3025 9.048187 9.713599 NA NA NA Nephropathy NA

535 TIMM44 7.914812 8.610034 8.173936 8.404338 NA NA NA Nephropathy NA

536 TIMP1 10.3686 12.84306 11.26313 12.06622 NA Retinopathy NA NA NA

537 TIMP2 8.392464 9.54184 8.74861 9.151211 NA NA NA Nephropathy NA

538 TIMP3 9.617132 10.67626 10.05077 10.38914 NA Retinopathy Atherosclerosis Nephropathy NA

539 TKT 7.536227 9.430602 8.200657 8.754219 NA NA NA Nephropathy Neuropathy

540 TLR2 6.122348 7.544432 6.545776 6.983771 NA NA NA Nephropathy NA

541 TLR4 6.84616 7.668132 7.157797 7.433589 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

542 TM6SF2 6.182352 6.681151 6.313779 6.471758 Cardiovascular NA NA NA NA diseases 543 TNF 5.970589 6.971744 6.296317 6.626552 NA Retinopathy NA Nephropathy Neuropathy

544 TNFAIP8 7.251628 8.438567 7.513153 7.90915 NA NA NA Nephropathy NA

545 TNFRSF1 6.455231 11.15132 7.482865 8.829785 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy 1B diseases 546 TNFRSF1 6.917004 7.634403 7.127008 7.363229 NA NA NA NA Neuropathy B 547 TPM1 10.7573 11.81834 10.99795 11.37737 Cardiovascular NA NA NA NA diseases 548 TRAF6 7.832585 9.104816 8.190229 8.566216 NA NA NA NA Neuropathy

549 TRH 6.56274 7.685748 6.949132 7.304795 NA NA NA NA Neuropathy

550 TRIB3 6.31395 7.093167 6.6037 6.816734 Cardiovascular NA NA Nephropathy NA diseases 551 TRPA1 5.009615 5.618739 5.24116 5.437692 NA NA NA NA Neuropathy

552 TRPC1 7.676386 8.969409 8.200062 8.633974 NA NA NA Nephropathy NA

553 TRPC6 5.547391 6.489607 5.786263 6.085342 NA NA Atherosclerosis Nephropathy NA

554 TRPV1 6.797945 7.771756 7.104125 7.437257 NA NA NA NA Neuropathy

555 TRPV4 5.707356 6.407734 5.922317 6.129745 NA NA NA Nephropathy NA

556 TSC1 8.310266 9.199686 8.593901 8.895379 NA NA NA Nephropathy NA

557 TSC2 7.432171 7.992885 7.659497 7.852458 NA NA NA Nephropathy NA

558 TSC22D1 9.57399 10.90458 9.965924 10.34728 NA NA NA Nephropathy NA

559 TSPO 8.435629 9.303856 8.85745 9.137817 NA NA NA NA Neuropathy

560 TUBB3 7.933886 9.279178 8.388071 8.809452 NA Retinopathy NA NA NA

561 TXN 8.019498 9.371386 8.483937 8.938731 Cardiovascular NA Atherosclerosis NA NA diseases

100

562 TXNIP 9.434094 11.16106 10.12368 10.6791 NA Retinopathy Atherosclerosis Nephropathy NA

563 UCP1 4.971637 5.736379 5.22234 5.454211 NA Retinopathy NA NA NA

564 UCP2 7.333475 8.746647 7.775398 8.210553 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

565 UMOD 5.999678 6.490068 6.145584 6.31334 NA NA NA Nephropathy NA

566 UNC13A 5.344481 6.043846 5.533085 5.768045 NA NA NA NA Neuropathy

567 UNC13B 7.83951 8.571965 7.985394 8.238546 NA NA NA Nephropathy NA

568 UNC5B 7.244492 8.453044 7.642689 8.038198 NA NA NA Nephropathy NA

569 USF2 8.764838 9.66957 9.058681 9.371026 NA NA NA Nephropathy NA

570 UTRN 7.961457 9.002521 8.281505 8.585868 NA NA NA Nephropathy NA

571 UTS2 4.612717 5.227484 4.704392 4.898779 NA Retinopathy Atherosclerosis NA NA

572 VCAM1 6.029447 7.786094 6.460477 7.059087 Cardiovascular NA Atherosclerosis NA NA diseases 573 VDAC1 8.816406 9.328848 8.932961 9.121919 NA NA NA Nephropathy NA

574 VDAC2 8.440777 9.224435 8.658611 8.876688 NA NA NA Nephropathy NA

575 VDR 5.804942 6.741249 6.041285 6.356155 Cardiovascular Retinopathy NA Nephropathy NA diseases 576 VEGFA 7.826522 9.12538 8.216501 8.569014 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

577 VEGFC 6.643198 7.859896 7.032815 7.433962 NA Retinopathy NA NA NA

578 VIP 5.116546 6.10398 5.367431 5.671652 NA NA NA NA Neuropathy

579 VWF 7.644838 9.753527 8.395268 9.2046 Cardiovascular NA NA Nephropathy Neuropathy diseases 580 WFS1 8.127156 9.666264 8.755995 9.28371 NA NA NA Nephropathy NA

581 WT1 6.129955 6.495455 6.250364 6.365024 NA NA NA Nephropathy NA

582 XBP1 8.621276 10.53684 9.065443 9.608069 NA NA NA Nephropathy NA

583 XIAP 6.122073 6.745006 6.416813 6.622985 NA NA NA NA Neuropathy

584 XRCC1 7.521772 8.135293 7.66381 7.845328 Cardiovascular Retinopathy NA NA NA diseases 585 ZEB2 9.075727 10.01726 9.316087 9.624852 NA NA NA Nephropathy NA

586 ZNF236 6.763528 7.198865 6.956577 7.07607 NA NA NA Nephropathy NA

Table A.4: table for liver tissue

Genes Actual Actual 99% CI 99% CI complication1 complication2 complication3 complication4 complication5 Min Max Min Max 1 ABCA1 0.525144 1.178044 0.512346 0.930424 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 2 ABCC11 0.241818 1.545914 0.338656 1.290525 NA NA NA Nephropathy NA

3 ABCG1 0.713815 1.878653 0.700336 1.447189 Cardiovascular NA Atherosclerosis NA NA diseases 4 ABO 0.438904 1.811046 0.364214 1.352386 Cardiovascular NA NA NA NA diseases 5 ACACB 0.75058 1.7444 0.794467 1.467981 NA NA NA Nephropathy NA

6 ACAT1 0.652835 1.523269 0.69499 1.371017 NA NA Atherosclerosis NA NA

7 ACE 0.184023 1.072877 0.264697 0.826003 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 8 ACE2 0.413356 1.211912 0.547372 1.106403 Cardiovascular NA NA Nephropathy NA diseases 9 ACSL1 0.634026 1.226542 0.709801 1.105449 NA NA Atherosclerosis NA NA

10 ACVR1C 0.615002 2.323211 0.699484 1.78551 Cardiovascular NA NA NA NA diseases 11 ACVRL1 0.390388 1.735945 0.356462 1.357055 NA NA NA Nephropathy NA

12 ADAM10 0.534504 1.214968 0.540096 1.066882 NA NA NA Nephropathy NA

13 ADAM17 0.627688 1.190432 0.631114 1.036028 NA NA Atherosclerosis Nephropathy NA

14 ADAMTS1 0.714967 1.503612 0.790394 1.428201 NA NA NA Nephropathy NA 3

101

15 ADCY5 0.306664 1.586774 0.24982 1.149749 Cardiovascular NA NA NA NA diseases 16 ADCYAP1 0.150888 1.308656 0.47184 1.158084 NA Retinopathy NA Nephropathy NA

17 ADH1B 0.676621 1.196853 0.749161 1.108591 NA NA NA Nephropathy Neuropathy

18 ADIPOQ 0.330273 1.203689 0.592598 1.167709 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 19 ADIPOR1 0.450067 1.30885 0.572985 1.213303 Cardiovascular NA NA NA NA diseases 20 ADK 0.536312 0.893132 0.632456 0.853366 NA Retinopathy NA NA NA

21 ADM 0.478532 1.120202 0.58418 1.082929 NA Retinopathy NA Nephropathy Neuropathy

22 ADRA2B 0.266185 1.645452 0.590563 1.544891 NA NA NA NA Neuropathy

23 AGER 0.518609 1.916923 0.667329 1.808059 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 24 AGT 0.772499 1.432933 0.878705 1.399687 NA NA NA Nephropathy Neuropathy

25 AGTR1 0.410821 1.137945 0.668847 1.145025 NA NA NA Nephropathy NA

26 AGXT2 0.677217 1.771385 0.746277 1.485518 Cardiovascular NA NA NA NA diseases 27 AHRR 0.293371 1.510922 0.467865 1.320119 NA Retinopathy NA NA NA

28 AHSA1 0.61597 1.313548 0.650737 1.179925 Cardiovascular Retinopathy NA Nephropathy NA diseases 29 AHSG 0.715594 1.275416 0.852858 1.323969 Cardiovascular Retinopathy NA Nephropathy NA diseases 30 AKR1B1 0.707137 1.924258 0.572805 1.397195 NA Retinopathy NA Nephropathy Neuropathy

31 AKR1B10 0.281638 2.593801 0.17031 2.140618 NA NA NA Nephropathy NA

32 AKT1 0.329448 1.406073 0.586325 1.354063 Cardiovascular Retinopathy NA Nephropathy NA diseases 33 ALB 0.655063 1.504597 0.81956 1.442619 NA NA Atherosclerosis Nephropathy Neuropathy

34 ALDH1A1 0.482368 1.236638 0.671142 1.193419 NA NA NA Nephropathy NA

35 ALDH2 0.710694 1.34992 0.755632 1.231059 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 36 ALOX5AP 0.57703 1.725912 0.55654 1.34646 NA NA Atherosclerosis Nephropathy NA

37 ALPK1 0.238729 1.757029 0.521267 1.470091 Cardiovascular NA NA NA NA diseases 38 ALPL 0.745203 3.042724 0.513499 2.082962 NA NA NA Nephropathy NA

39 AMBP 0.561798 1.403387 0.754346 1.407798 NA NA NA Nephropathy NA

40 ANG 0.722663 1.234403 0.762674 1.124619 NA NA NA Nephropathy NA

41 ANGPT2 0.380016 1.316554 0.529776 1.169755 NA Retinopathy NA NA NA

42 ANGPTL2 0.444259 1.498092 0.569047 1.205588 NA NA Atherosclerosis Nephropathy NA

43 ANGPTL4 0.534661 2.054988 0.715531 1.945789 NA Retinopathy NA Nephropathy NA

44 AOC2 0.695658 1.58268 0.764125 1.39498 NA NA NA Nephropathy NA

45 AOC3 0.548577 1.347314 0.624581 1.116121 NA Retinopathy NA NA NA

46 APC 0.596329 1.150385 0.656331 1.077262 NA NA NA Nephropathy NA

47 API5 0.523194 1.339084 0.627375 1.146445 NA Retinopathy NA NA NA

48 APLN 0.691389 2.362828 1.053866 2.322975 NA NA NA NA Neuropathy

49 APLNR 0.52691 1.451854 0.68639 1.334351 NA NA NA Nephropathy NA

50 APOA1 0.672349 1.648982 0.843834 1.622075 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 51 APOA5 0.640419 3.236448 0.422129 2.552028 Cardiovascular NA Atherosclerosis NA NA diseases 52 APOB 0.672496 1.923042 0.611411 1.467244 Cardiovascular Retinopathy NA NA Neuropathy diseases 53 APOC1 0.660329 1.593362 0.85498 1.550039 NA NA NA Nephropathy NA

54 APOC3 0.674514 1.366117 0.778258 1.297822 Cardiovascular NA NA Nephropathy NA diseases 55 APOE 0.863588 2.14791 0.951033 1.901637 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 56 APOH 0.707819 1.512005 0.88112 1.519237 Cardiovascular NA NA NA NA diseases 57 APOL1 0.756488 1.465836 0.765423 1.259142 Cardiovascular NA NA Nephropathy NA diseases 58 APOM 0.754016 1.650967 0.974793 1.599638 NA NA Atherosclerosis NA NA

102

59 APPL1 0.535999 0.983127 0.6268 0.978911 NA NA Atherosclerosis Nephropathy NA

60 AQP1 0.646539 1.459601 0.648928 1.191748 NA Retinopathy NA NA NA

61 AQP4 0.103488 0.657165 0.094387 0.478972 NA Retinopathy NA NA NA

62 AQP5 0.370628 2.043671 0.384686 1.479846 NA NA NA Nephropathy NA

63 AR 0.837685 1.265976 0.917639 1.174196 NA NA NA Nephropathy NA

64 ASPA 0.601853 2.904505 0.508767 2.032614 NA NA NA NA Neuropathy

65 ATF4 0.740004 1.230598 0.786814 1.146025 NA Retinopathy NA Nephropathy NA

66 ATM 0.859562 1.096512 0.848758 1.008099 Cardiovascular NA NA NA NA diseases 67 ATP2A2 0.633444 1.280337 0.823191 1.225922 NA NA NA NA Neuropathy

68 B2M 0.614068 1.192756 0.75505 1.198081 NA NA Atherosclerosis Nephropathy NA

69 BAAT 0.466395 1.332671 0.692948 1.269843 NA NA Atherosclerosis NA NA

70 BAMBI 0.472585 1.417708 0.517022 1.140609 NA NA NA Nephropathy NA

71 BASP1 0.47809 1.49147 0.623575 1.381535 NA NA NA Nephropathy NA

72 BCL2 0.426311 1.419848 0.495936 1.122959 NA NA NA Nephropathy NA

73 BCO2 0.831981 2.518825 0.727749 1.854604 Cardiovascular NA NA NA NA diseases 74 BDKRB1 0.261578 1.879775 0.549359 1.78033 NA NA NA NA Neuropathy

75 BDKRB2 0.167925 2.643233 -0.24388 1.497472 NA NA NA NA Neuropathy

76 BDNF 0.167293 1.039349 0.137395 0.730424 NA Retinopathy NA NA Neuropathy

77 BMP2 0.418895 1.55237 0.678262 1.391562 NA NA Atherosclerosis NA NA

78 BMP4 0.44419 1.470605 0.75798 1.376129 NA NA NA Nephropathy NA

79 BNIP3 0.758126 1.278388 0.78932 1.169487 Cardiovascular NA NA NA NA diseases 80 C5 0.661547 1.347703 0.738385 1.183324 NA Retinopathy NA Nephropathy NA

81 CACNA1 0.793238 1.934978 0.923077 1.85662 NA NA NA NA Neuropathy H 82 CAPN10 0.593227 2.283804 0.518179 1.860591 NA NA Atherosclerosis NA NA

83 CAT 0.70172 1.164225 0.863979 1.212607 NA Retinopathy NA Nephropathy NA

84 CAV1 0.627688 1.134219 0.689956 1.032323 NA NA NA Nephropathy Neuropathy

85 CCK 0.12168 2.024248 -0.12357 1.289944 NA NA NA Nephropathy Neuropathy

86 CCKAR 0.209906 1.819623 0.372387 1.452623 NA NA NA Nephropathy NA

87 CCL2 0.224398 1.456983 0.186185 1.140072 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

88 CCL20 0.104953 0.463288 0.173548 0.40157 NA NA NA Nephropathy NA

89 CCL5 0.632416 2.384099 0.4867 1.731544 NA NA NA Nephropathy NA

90 CCR1 0.499716 1.03672 0.598157 1.013147 NA NA NA Nephropathy NA

91 CCR2 0.578217 1.442215 0.772312 1.340869 NA NA Atherosclerosis Nephropathy NA

92 CCR5 0.340332 1.930074 0.338586 1.369796 NA NA Atherosclerosis Nephropathy NA

93 CD160 0.505079 1.08245 0.626738 0.994088 NA Retinopathy NA NA NA

94 CD163 0.478033 1.128619 0.582627 1.009309 NA Retinopathy Atherosclerosis NA Neuropathy

95 CD247 0.237451 1.262935 0.528277 1.194701 Cardiovascular NA NA NA NA diseases 96 CD2AP 0.723716 1.58776 0.792198 1.406206 NA NA NA Nephropathy NA

97 CD34 0.320799 2.43181 0.479265 1.857199 NA NA NA NA Neuropathy

98 CD36 0.629717 1.047565 0.697648 0.963895 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 99 CD38 0.29019 1.051274 0.433025 1.075672 NA NA NA Nephropathy NA

100 CD4 0.223659 1.192926 0.445709 1.003941 Cardiovascular NA Atherosclerosis NA NA diseases 101 CD40 0.813534 1.385856 0.977143 1.348393 Cardiovascular NA Atherosclerosis NA NA diseases 102 CD40LG 0.719361 1.460156 0.803109 1.33797 Cardiovascular NA NA Nephropathy NA diseases

103

103 CD47 0.77635 1.087753 0.78875 1.026437 NA NA NA Nephropathy NA

104 CD59 0.63358 1.243867 0.686547 1.101764 NA Retinopathy NA NA NA

105 CD63 0.725261 1.254024 0.813272 1.181849 NA NA NA Nephropathy NA

106 CD68 0.710256 1.608016 0.729103 1.424348 NA NA NA Nephropathy NA

107 CD69 0.581958 0.952668 0.633711 0.903179 NA NA NA Nephropathy NA

108 CD74 0.708899 1.840736 0.640931 1.396036 NA NA NA Nephropathy NA

109 CD80 0.573633 1.392147 0.600269 1.248259 NA NA NA Nephropathy NA

110 CD9 0.392934 1.739606 0.612418 1.423578 Cardiovascular NA NA NA NA diseases 111 CDC123 0.69656 1.235611 0.717564 1.137218 Cardiovascular NA NA NA NA diseases 112 CDH1 0.578048 1.266756 0.754096 1.259103 NA NA NA Nephropathy NA

113 CDH2 0.533746 1.318064 0.610021 1.211281 NA NA NA Nephropathy NA

114 CDK7 0.525236 1.366801 0.560561 1.208577 NA NA NA Nephropathy NA

115 CDKAL1 0.252296 0.792692 0.372093 0.720076 Cardiovascular NA NA Nephropathy NA diseases 116 CDKN1A 0.653423 1.962667 0.652732 1.530214 NA NA NA Nephropathy NA

117 CDKN2A 0.554726 1.335 0.507258 1.033004 Cardiovascular NA NA NA NA diseases 118 CETP 0.426909 1.246286 0.470933 1.046672 Cardiovascular NA Atherosclerosis NA NA diseases 119 CHI3L1 0.267376 2.579624 0.138827 1.864377 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 120 CHIT1 0.209906 0.75282 0.19761 0.567285 NA NA NA Nephropathy NA

121 CHN2 0.559858 1.337213 0.69283 1.341038 NA Retinopathy NA Nephropathy NA

122 CHPT1 0.726902 1.347645 0.764934 1.244956 NA NA NA Nephropathy NA

123 CISH 0.413627 1.238746 0.590793 1.201223 NA NA NA Nephropathy NA

124 CITED2 0.580575 1.272802 0.577942 1.037285 NA NA Atherosclerosis NA NA

125 CLCN5 0.813553 1.218265 0.863608 1.167467 NA NA NA Nephropathy NA

126 CLEC11A 0.936136 1.91652 1.008876 1.798639 NA NA NA Nephropathy NA

127 CLOCK 0.700167 1.113752 0.772236 1.057279 Cardiovascular NA NA NA NA diseases 128 CMA1 0.208431 1.425391 0.132041 1.251143 NA NA NA Nephropathy NA

129 CMC4 0.920599 1.399255 0.963241 1.270524 NA NA NA Nephropathy NA

130 CNDP1 0.664451 1.785373 0.60897 1.428001 Cardiovascular NA NA Nephropathy NA diseases 131 CNDP2 0.763904 1.221007 0.807688 1.115474 NA NA NA Nephropathy NA

132 CNR1 0.425879 1.27521 0.57492 1.143596 NA Retinopathy NA Nephropathy Neuropathy

133 CNR2 0.180069 1.770156 0.536529 1.478002 NA NA NA Nephropathy Neuropathy

134 CNTF 0.427297 1.178322 0.65917 1.169511 NA NA NA NA Neuropathy

135 COG2 0.613528 1.806527 0.689708 1.484374 NA NA Atherosclerosis NA NA

136 COL8A1 0.440802 1.090126 0.579375 1.01093 NA NA NA Nephropathy NA

137 COL8A2 0.639293 1.371753 0.742422 1.348022 NA NA NA Nephropathy NA

138 COLEC12 0.536686 1.636454 0.63338 1.326893 NA Retinopathy NA NA NA

139 COMT 0.624284 1.456443 0.755273 1.283068 Cardiovascular NA NA NA NA diseases 140 CPVL 0.303427 1.24842 0.484207 1.155135 NA NA NA Nephropathy NA

141 CRH 0.451681 1.550711 0.612474 1.344549 NA NA NA NA Neuropathy

142 CRK 0.802372 1.675366 0.79225 1.40571 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 143 CRP 0.427291 2.974464 0.413822 2.102318 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 144 CST3 0.463505 0.948715 0.656916 0.970342 Cardiovascular NA NA NA NA diseases 145 CTGF 0.092139 1.898769 0.286386 1.633847 NA Retinopathy NA Nephropathy NA

146 CTSH 0.523835 1.554668 0.752428 1.404612 NA Retinopathy NA NA NA

104

147 CTSS 0.431147 1.440413 0.395631 1.055939 Cardiovascular NA NA NA NA diseases 148 CUBN 0.136923 1.182603 0.081532 0.824476 NA NA NA Nephropathy NA

149 CX3CL1 0.658471 2.18773 0.830227 1.882455 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 150 CX3CR1 0.584666 1.257894 0.757673 1.171916 NA NA NA Nephropathy NA

151 CXCL10 0.545265 2.402128 0.440255 1.759131 NA NA NA Nephropathy Neuropathy

152 CXCL11 0.382771 0.992679 0.480462 0.912164 NA NA NA Nephropathy NA

153 CXCL12 0.56049 1.225058 0.694539 1.102212 NA NA NA Nephropathy NA

154 CXCL16 0.508283 1.528807 0.564386 1.261568 NA NA NA Nephropathy NA

155 CXCL5 0.206977 0.629717 0.219788 0.539141 NA NA Atherosclerosis Nephropathy NA

156 CXCL8 0.2675 1.485895 0.343745 1.139459 NA NA NA Nephropathy NA

157 CXCL9 0.2144 1.306682 0.361808 1.282142 NA NA NA Nephropathy NA

158 CYBA 0.535258 1.877112 0.608267 1.507671 NA NA Atherosclerosis Nephropathy NA

159 CYBB 0.538048 1.304346 0.653948 1.142843 NA Retinopathy NA NA NA

160 CYP1A1 0.757247 3.128993 0.451397 2.179296 Cardiovascular NA Atherosclerosis NA NA diseases 161 CYP24A1 0.669173 1.316712 0.730965 1.171384 NA NA NA Nephropathy NA

162 CYP2C19 0.718251 2.161135 0.73299 1.772779 NA Retinopathy NA NA NA

163 CYP2J2 0.489982 1.777411 0.487604 1.320896 Cardiovascular NA NA Nephropathy NA diseases 164 CYP7A1 0.112913 1.850393 0.316879 1.747813 Cardiovascular NA NA NA NA diseases 165 CYR61 0.38034 1.111007 0.325201 0.908155 NA Retinopathy NA NA NA

166 DCXR 0.724554 1.668761 0.848375 1.52976 NA NA NA Nephropathy NA

167 DDAH1 0.573455 1.125411 0.59677 0.998514 NA Retinopathy NA Nephropathy NA

168 DDIT3 0.833343 1.235367 0.878035 1.187589 Cardiovascular NA NA Nephropathy Neuropathy diseases 169 DEFA1 0.304013 2.957261 0.071659 1.882114 NA NA NA Nephropathy NA

170 DES 0.425031 5.91008 -0.24937 3.547601 NA NA NA Nephropathy NA

171 DGKH 0.724995 1.171053 0.770135 1.068553 NA NA NA Nephropathy NA

172 DHCR7 0.644981 1.476501 0.692955 1.242457 NA NA Atherosclerosis NA NA

173 DKK1 0.65195 1.982171 0.665363 1.592182 Cardiovascular Retinopathy NA Nephropathy NA diseases 174 DNMT1 0.710861 1.689554 0.718463 1.357439 NA NA NA Nephropathy NA

175 DPP4 0.490091 1.409223 0.656777 1.242642 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 176 DSEL 0.440802 1.164244 0.558504 1.015654 NA NA NA Nephropathy NA

177 EBF1 0.194666 1.240865 0.37733 1.060903 Cardiovascular NA NA NA NA diseases 178 EBF2 0.100376 1.164315 0.059916 0.970152 NA NA NA Nephropathy NA

179 EDN1 0.766708 1.336316 0.897345 1.292653 NA Retinopathy NA Nephropathy Neuropathy

180 EDNRA 0.429785 1.461391 0.53749 1.31001 NA NA NA Nephropathy NA

181 EGF 0.896195 2.250623 0.778309 1.731007 NA NA NA Nephropathy NA

182 EGFR 0.732951 1.608347 0.62395 1.340922 Cardiovascular NA NA Nephropathy NA diseases 183 EIF2AK3 0.408425 1.12954 0.482137 0.964167 NA NA NA Nephropathy NA

184 EIF4EBP 0.654592 1.925363 0.835427 1.744159 NA NA NA Nephropathy NA 1 185 ELMO1 0.352773 1.902431 0.512541 1.614733 NA NA NA Nephropathy NA

186 ELN 0.413372 1.894583 0.756887 1.648503 NA NA Atherosclerosis NA NA

187 ENG 0.208594 0.521077 0.254516 0.483438 Cardiovascular Retinopathy NA NA Neuropathy diseases 188 ENPP1 0.701556 1.10621 0.774339 1.092877 NA NA NA Nephropathy NA

189 ENPP2 0.459931 1.63317 0.536418 1.374936 NA NA NA NA Neuropathy

190 ENTPD1 0.492671 1.090153 0.526906 0.971515 NA NA Atherosclerosis Nephropathy NA

105

191 EPO 0.494987 1.411747 0.724278 1.417401 NA Retinopathy NA Nephropathy Neuropathy

192 EPOR 0.663471 1.256037 0.750092 1.146391 NA NA NA Nephropathy NA

193 ERAP2 0.138505 1.19517 0.202712 1.042347 NA Retinopathy NA NA NA

194 ERBB2 0.368045 1.859961 0.473309 1.421607 Cardiovascular NA NA NA Neuropathy diseases 195 ERBB3 0.772568 1.620474 0.778811 1.399815 NA Retinopathy NA NA NA

196 ERBB4 0.538443 1.714566 0.675897 1.549258 NA NA NA Nephropathy NA

197 ERCC1 0.694938 1.461767 0.868461 1.424268 NA Retinopathy NA Nephropathy NA

198 ERCC4 0.309209 1.435788 0.497059 1.42029 NA Retinopathy NA Nephropathy NA

199 ERRFI1 0.662479 1.378529 0.731967 1.239051 NA NA NA Nephropathy NA

200 ESAM 0.75173 1.44935 0.808865 1.262557 NA NA NA Nephropathy NA

201 ESM1 0.270153 1.448189 0.407639 1.212453 NA NA NA NA Neuropathy

202 ESR1 0.498096 0.850081 0.54138 0.814472 NA NA NA Nephropathy NA

203 EXOSC7 0.827836 1.332564 0.841766 1.180478 NA NA NA Nephropathy NA

204 EZR 0.522746 1.268175 0.51944 1.095306 NA NA NA Nephropathy NA

205 F11 0.75139 1.710975 0.773731 1.52335 NA NA NA Nephropathy NA

206 F2R 0.550085 2.253477 0.587941 1.679384 NA NA NA Nephropathy NA

207 F8 0.38056 1.246329 0.484296 1.078142 NA NA NA NA Neuropathy

208 FABP1 0.723484 1.527958 0.675586 1.221946 Cardiovascular NA NA Nephropathy NA diseases 209 FABP2 0.336337 2.71015 0.040216 1.664745 NA NA NA Nephropathy NA

210 FABP4 0.458438 3.769967 0.049654 2.773098 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 211 FABP5 0.052374 3.54128 0.143929 2.634344 Cardiovascular NA Atherosclerosis NA NA diseases 212 FADS1 0.347525 1.933296 0.547367 1.770449 Cardiovascular NA NA NA NA diseases 213 FADS2 0.509789 2.177845 0.721166 1.796637 Cardiovascular NA NA NA NA diseases 214 FASN 0.303902 2.871738 0.431892 2.35989 NA NA NA Nephropathy NA

215 FBXO8 0.385424 1.554441 0.509497 1.295548 NA Retinopathy NA NA NA

216 FFAR1 0.124966 1.155288 0.084321 0.832971 NA Retinopathy NA NA NA

217 FFAR2 0.208594 0.944575 0.252116 0.760077 Cardiovascular NA NA NA NA diseases 218 FGF19 0.267669 1.826179 0.044971 1.120363 Cardiovascular NA NA NA NA diseases 219 FGF21 0.343524 1.222419 0.442348 1.143694 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 220 FGF23 0.251887 2.302616 0.58642 2.055324 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 221 FGFR1 0.801081 1.174221 0.937162 1.197399 NA NA Atherosclerosis NA NA

222 FKBP10 0.171955 3.064622 -0.268 1.789246 Cardiovascular NA NA NA NA diseases 223 FKBP2 0.485562 1.534297 0.580168 1.259723 NA NA Atherosclerosis NA NA

224 FKBP4 0.489803 0.989252 0.465066 0.83358 Cardiovascular NA NA NA NA diseases 225 FKBP8 0.601624 1.804834 0.796718 1.62046 Cardiovascular NA NA NA NA diseases 226 FMO3 0.698134 1.436865 0.731703 1.292517 NA NA Atherosclerosis NA NA

227 FMOD 0.768573 1.20224 0.83595 1.16341 NA NA Atherosclerosis NA NA

228 FN3K 0.117105 2.509593 -0.06529 1.786729 NA NA NA Nephropathy NA

229 FOLH1 0.780155 1.297272 0.877012 1.227434 NA NA NA NA Neuropathy

230 FOS 0.125059 3.21582 -0.34839 2.221764 NA NA NA Nephropathy NA

231 FOXA2 0.552068 1.195234 0.616391 1.078085 NA NA Atherosclerosis NA NA

232 FOXO1 0.570234 1.373959 0.60077 1.200072 NA NA Atherosclerosis NA NA

233 FOXO4 0.178613 2.262793 0.345066 2.175366 NA NA NA Nephropathy NA

234 FPR1 0.580239 0.859414 0.58676 0.773981 NA NA Atherosclerosis NA NA

106

235 FRMD3 0.31089 1.259875 0.43685 1.089087 NA Retinopathy NA Nephropathy NA

236 FTO 0.693007 1.553325 0.82674 1.417431 Cardiovascular NA NA Nephropathy NA diseases 237 G6PD 0.155233 3.316509 0.01763 2.271497 Cardiovascular NA NA Nephropathy Neuropathy diseases 238 GAP43 0.374962 1.272759 0.643507 1.219026 NA NA NA NA Neuropathy

239 GAPDH 0.812491 1.620126 0.832363 1.483895 NA Retinopathy NA NA Neuropathy

240 GAS1 0.120431 0.782456 0.143717 0.598282 NA NA NA Nephropathy NA

241 GAS6 0.481971 1.252437 0.623279 1.192173 NA NA NA Nephropathy NA

242 GCG 0.077616 1.406909 0.229677 1.363165 NA NA NA Nephropathy NA

243 GCK 0.050102 2.951775 -0.07644 2.330275 NA NA NA Nephropathy Neuropathy

244 GCKR 0.722909 2.608685 0.849971 2.010474 Cardiovascular NA NA NA NA diseases 245 GDF15 0.230896 0.764777 0.228671 0.640251 Cardiovascular NA NA Nephropathy NA diseases 246 GDNF 0.219184 1.088196 0.355574 0.927094 NA Retinopathy NA NA Neuropathy

247 GFAP 0.133835 0.413953 0.135287 0.321133 NA NA NA NA Neuropathy

248 GFPT1 0.838997 1.618451 0.789123 1.331323 NA NA NA Nephropathy NA

249 GFPT2 0.362472 1.575906 0.481069 1.363986 NA NA NA Nephropathy NA

250 GGT1 0.475864 1.951648 0.62265 1.588537 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 251 GHR 0.682367 1.184899 0.728189 1.124613 NA NA NA Nephropathy NA

252 GHRL 0.807424 1.394603 0.848566 1.340889 Cardiovascular NA NA Nephropathy NA diseases 253 GHSR 0.170685 0.975577 0.134451 0.675465 NA NA NA Nephropathy NA

254 GIP 0.446394 1.781179 0.709042 1.602217 Cardiovascular NA Atherosclerosis NA Neuropathy diseases 255 GIPR 0.37373 1.180962 0.353402 0.944637 NA Retinopathy NA NA Neuropathy

256 GK 0.551791 1.651323 0.759337 1.403043 Cardiovascular NA NA NA NA diseases 257 GLO1 0.71319 1.202718 0.77969 1.112934 NA NA Atherosclerosis Nephropathy Neuropathy

258 GLP1R 0.362209 1.056816 0.496622 1.002386 Cardiovascular NA NA NA Neuropathy diseases 259 GLUL 0.603326 1.516892 0.612585 1.258592 Cardiovascular NA NA NA NA diseases 260 GNB3 0.675599 1.391979 0.818746 1.371473 NA NA NA Nephropathy NA

261 GORAB 0.484856 1.033801 0.549397 0.952501 NA Retinopathy NA NA NA

262 GPC5 0.669386 1.420913 0.923631 1.456243 NA NA NA Nephropathy NA

263 GPX1 0.835181 1.109444 0.840944 1.038683 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 264 GRB2 0.855565 1.33765 0.921789 1.262959 NA Retinopathy NA NA NA

265 GREM1 0.036817 2.358833 0.100659 1.873717 NA NA NA Nephropathy NA

266 GSTM1 0.575318 11.32821 0.87565 9.595848 NA Retinopathy Atherosclerosis Nephropathy NA

267 GSTT1 0.042965 1.622488 0.318112 1.567276 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 268 GYS1 0.769601 2.001732 0.683395 1.613573 Cardiovascular NA NA NA NA diseases 269 HBG2 0.39036 7.065273 0.032637 4.403297 NA Retinopathy NA NA NA

270 HCN2 0.61366 1.727911 0.769403 1.681425 NA NA NA NA Neuropathy

271 HDAC4 0.582742 1.225257 0.618136 1.105119 NA NA NA Nephropathy NA

272 HDAC9 0.281382 1.174857 0.34339 0.968353 NA NA Atherosclerosis NA NA

273 HFE 0.639317 1.053075 0.750961 1.049086 NA Retinopathy NA Nephropathy NA

274 HGF 0.312051 0.938464 0.498779 0.878763 NA NA Atherosclerosis Nephropathy Neuropathy

275 HHEX 0.499908 1.244075 0.610648 1.114873 Cardiovascular NA NA Nephropathy NA diseases 276 HIF1A 0.595824 1.139888 0.681397 1.03572 Cardiovascular NA NA Nephropathy NA diseases 277 HLA-A 0.615505 1.942206 0.76699 1.5624 NA NA NA Nephropathy NA

278 HLA- 0.479835 1.617288 0.622731 1.366269 NA NA NA Nephropathy NA DQA1

107

279 HMCN1 0.410709 0.940696 0.553318 0.911922 NA NA NA Nephropathy NA

280 HMGA2 0.325192 1.495036 0.406685 1.218045 NA NA NA Nephropathy NA

281 HMGB1 0.74083 1.177579 0.774143 1.097351 Cardiovascular Retinopathy NA Nephropathy NA diseases 282 HMGCS2 0.698108 1.492705 0.801348 1.325502 NA NA NA Nephropathy NA

283 HMOX1 0.503123 1.229048 0.578624 1.024147 NA NA NA Nephropathy NA

284 HNF1A 0.908495 2.527751 0.866414 1.922456 NA NA NA Nephropathy NA

285 HNF1B 0.48575 1.290976 0.649675 1.249266 Cardiovascular NA NA NA NA diseases 286 HNF4A 0.517142 1.072228 0.687226 1.088136 Cardiovascular NA NA NA NA diseases 287 HP 0.592609 1.53949 0.79874 1.500978 Cardiovascular NA Atherosclerosis NA NA diseases 288 HPSE 0.149086 1.272803 0.287636 1.231956 NA NA NA Nephropathy NA

289 HRH1 0.430976 1.331741 0.746357 1.369814 NA NA NA NA Neuropathy

290 HRH2 0.322365 2.310325 1.014645 2.331604 NA NA NA NA Neuropathy

291 HS6ST3 0.21165 0.872804 0.231245 0.660269 NA Retinopathy NA NA NA

292 HSPA1A 0.58579 1.252804 0.790023 1.229166 NA NA NA Nephropathy NA

293 HSPA1B 0.484012 1.993778 0.603178 1.633722 NA NA NA Nephropathy NA

294 HSPA5 0.878265 1.276351 0.928569 1.23848 NA NA NA NA Neuropathy

295 HSPB1 0.718203 1.996455 0.746592 1.661656 NA NA NA Nephropathy NA

296 HSPG2 0.264273 3.527794 0.098081 2.426811 NA NA NA Nephropathy NA

297 HTR2A 0.451692 1.474709 0.605852 1.294939 NA NA NA Nephropathy NA

298 HYOU1 0.848059 2.262934 0.760789 1.739865 NA NA NA Nephropathy Neuropathy

299 ICAM1 0.589145 1.034603 0.664151 1.043989 NA NA Atherosclerosis Nephropathy NA

300 ID1 0.247868 1.127556 0.293291 1.066678 NA NA NA Nephropathy NA

301 IFNG 0.078366 1.884814 0.315467 1.576507 NA NA NA Nephropathy Neuropathy

302 IGF1 0.651787 1.204941 0.719848 1.142492 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 303 IGF1R 0.560962 1.759302 0.65204 1.523804 NA Retinopathy NA NA NA

304 IGF2 0.952747 1.810991 0.911292 1.543872 NA Retinopathy NA Nephropathy Neuropathy

305 IGFBP1 0.186177 2.548688 0.137853 1.703589 NA NA NA Nephropathy NA

306 IGFBP3 0.284131 1.150694 0.503573 1.159539 NA NA NA Nephropathy NA

307 IGFBP5 0.460249 1.240037 0.493182 1.109509 NA NA NA NA Neuropathy

308 IGFBP7 0.463008 0.952101 0.586555 0.952426 NA NA NA Nephropathy NA

309 IL10 0.066917 1.973113 0.186412 1.77941 NA NA NA Nephropathy Neuropathy

310 IL17A 0.125943 1.432534 -0.01935 0.934048 NA Retinopathy NA Nephropathy NA

311 IL18 0.066784 1.28102 0.216798 1.102849 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 312 IL1B 0.34699 1.140599 0.487834 0.940398 Cardiovascular Retinopathy NA Nephropathy NA diseases 313 IL1RN 0.53705 1.078234 0.60356 1.015213 NA NA NA Nephropathy NA

314 IL4 0.130371 1.109894 0.241433 0.973055 NA NA NA NA Neuropathy

315 IL6 0.206714 1.92519 -0.06516 1.334664 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

316 ILK 0.827769 1.78145 0.768025 1.553252 NA NA NA Nephropathy NA

317 INS 0.097534 0.49157 0.064651 0.329921 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 318 IRAK1 0.661166 1.356116 0.900232 1.322425 NA NA NA NA Neuropathy

319 IRAK4 0.794361 1.450337 0.873039 1.405711 NA NA Atherosclerosis NA NA

320 IRS1 0.708944 1.421005 0.729498 1.178873 NA Retinopathy NA NA NA

321 IRS2 0.595462 2.176137 0.696979 1.775241 NA NA Atherosclerosis Nephropathy Neuropathy

322 ITGA2 0.138942 1.21364 0.251065 0.955254 NA Retinopathy NA NA NA

108

323 ITGAM 0.813662 1.606692 0.926136 1.512152 NA Retinopathy NA Nephropathy NA

324 ITGB3 0.798239 1.232471 0.839966 1.13852 NA Retinopathy NA NA NA

325 JAK2 0.658356 1.180962 0.748409 1.094472 NA NA NA Nephropathy NA

326 JAZF1 0.454143 1.326541 0.725224 1.269388 Cardiovascular NA NA Nephropathy NA diseases 327 KCNJ11 0.262123 0.855769 0.341557 0.834791 NA Retinopathy NA NA Neuropathy

328 KCNQ1 0.445 1.106758 0.531414 1.054821 NA NA NA Nephropathy NA

329 KDM1A 0.981936 1.780048 0.991082 1.59797 NA Retinopathy NA NA NA

330 KL 0.314858 1.589286 0.463341 1.289928 NA NA NA Nephropathy NA

331 KLF10 0.403104 1.219074 0.498359 1.072775 NA NA NA Nephropathy NA

332 KLF6 0.591565 1.604582 0.584848 1.266722 NA NA NA Nephropathy NA

333 KMT2C 0.846061 1.365048 0.811904 1.192255 NA NA NA Nephropathy NA

334 L1CAM 0.136417 0.787189 0.236728 0.733376 NA Retinopathy NA NA NA

335 LAMC1 0.705478 1.151251 0.799644 1.092187 NA NA NA Nephropathy NA

336 LAP3 0.641543 1.113193 0.764219 1.072853 NA NA NA Nephropathy NA

337 LDLR 0.381831 1.207503 0.559264 1.151476 Cardiovascular NA Atherosclerosis NA NA diseases 338 LEP 0.077616 0.479231 0.129517 0.419016 NA NA Atherosclerosis NA Neuropathy

339 LIMK2 0.410254 1.497802 0.616834 1.311694 NA NA NA Nephropathy NA

340 LMNA 0.996746 1.58116 0.980767 1.417764 NA NA NA Nephropathy NA

341 LPA 0.233897 1.658744 0.44836 1.448447 Cardiovascular NA Atherosclerosis NA NA diseases 342 LPL 0.32527 3.23904 0.208656 2.562561 Cardiovascular NA Atherosclerosis Nephropathy Neuropathy diseases 343 LPO 0.158493 1.773047 0.216314 1.48687 NA Retinopathy NA NA NA

344 LRP2 0.312062 1.469047 0.420229 1.138056 NA NA NA Nephropathy NA

345 LTA 0.317857 2.920312 -0.04711 1.772888 NA NA NA Nephropathy NA

346 LTB4R2 0.314858 0.879651 0.254957 0.643379 NA Retinopathy NA NA NA

347 MAD2L2 0.599288 1.464213 0.555479 1.114568 NA NA NA Nephropathy NA

348 MAFB 0.783428 1.432649 0.874353 1.372665 Cardiovascular NA Atherosclerosis NA NA diseases 349 MALT1 0.69833 1.475303 0.805962 1.310249 NA NA NA Nephropathy NA

350 MAP3K5 0.739793 2.328044 0.617631 1.68777 Cardiovascular NA NA Nephropathy NA diseases 351 MAPK1 0.402417 0.997632 0.620184 1.015235 NA NA NA Nephropathy Neuropathy

352 MAPK14 0.508773 1.463261 0.590896 1.275537 NA NA NA Nephropathy NA

353 MAPK7 0.293658 2.312721 0.54875 1.813352 NA Retinopathy NA NA NA

354 MBL2 0.087025 1.288775 0.38195 1.197882 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 355 MBP 0.841206 1.121595 0.846345 1.048668 NA NA NA NA Neuropathy

356 MC4R 0.397412 1.261993 0.552665 1.158626 Cardiovascular NA NA Nephropathy NA diseases 357 MCAM 0.714858 1.481364 0.797597 1.260199 NA NA NA Nephropathy NA

358 MEP1B 0.253466 2.717052 0.457886 2.234059 NA NA NA Nephropathy NA

359 MIF 0.870798 1.355748 0.981804 1.30546 NA NA Atherosclerosis Nephropathy Neuropathy

360 MIOX 0.181105 1.250585 0.264395 1.146133 NA NA NA Nephropathy NA

361 MME 0.567844 1.81883 0.577244 1.390092 NA NA NA NA Neuropathy

362 MMP14 0.321582 1.46911 0.388044 1.119399 NA NA NA Nephropathy NA

363 MMP16 0.739538 1.565566 0.703599 1.23186 NA NA NA Nephropathy NA

364 MMP2 0.406692 1.160595 0.439545 1.023815 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 365 MMP24 0.237563 1.038821 0.318265 0.980205 NA NA NA Nephropathy NA

366 MMP9 0.200764 1.708974 0.412719 1.422698 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases

109

367 MOK 0.36127 1.575342 0.554861 1.394495 NA NA Atherosclerosis Nephropathy NA

368 MPO 0.480694 1.256428 0.515276 1.019517 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 369 MRPL28 0.889505 1.558966 0.932347 1.398541 NA Retinopathy NA NA NA

370 MSH2 0.201053 1.356343 0.51829 1.224081 Cardiovascular NA NA NA NA diseases 371 MTHFD1 0.457053 0.888064 0.49796 0.774284 Cardiovascular NA NA NA NA L diseases 372 MTHFR 0.729095 1.191245 0.871864 1.204041 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

373 MTOR 0.565329 2.024065 0.402768 1.433715 NA NA NA Nephropathy NA

374 MYD88 0.858557 1.550534 0.89945 1.458165 NA NA NA Nephropathy NA

375 MYH9 0.805264 1.369449 0.852724 1.220706 NA NA NA Nephropathy NA

376 MYO5C 0.635558 1.614098 0.707843 1.357161 NA Retinopathy NA NA NA

377 NAGLU 0.513056 1.46766 0.539489 1.166537 Cardiovascular Retinopathy NA NA NA diseases 378 NAMPT 0.722971 1.271281 0.710665 1.129271 Cardiovascular NA NA NA NA diseases 379 NCALD 0.469384 1.268945 0.615792 1.153193 NA NA NA Nephropathy NA

380 NCF1 0.036373 1.861067 0.405324 1.515684 NA NA NA Nephropathy NA

381 NCF2 0.122423 1.272783 0.503729 1.203459 NA NA NA Nephropathy NA

382 NDUFS3 0.959561 1.214714 0.946508 1.125765 NA NA NA Nephropathy NA

383 NEDD4L 0.660076 1.091103 0.764003 1.062536 NA NA NA Nephropathy NA

384 NFE2 0.349122 2.693421 0.071228 1.747172 NA NA NA Nephropathy NA

385 NFE2L2 0.585078 1.010228 0.576126 0.889898 NA Retinopathy NA Nephropathy Neuropathy

386 NFKBIA 0.791928 2.295356 0.780268 1.971755 NA NA NA Nephropathy NA

387 NGB 0.338834 1.251514 0.348929 0.941447 NA Retinopathy NA NA NA

388 NGF 0.267703 2.518575 0.183945 1.698398 NA NA NA Nephropathy Neuropathy

389 NGFR 0.642105 1.755409 0.719042 1.38481 NA NA NA NA Neuropathy

390 NLRP3 0.117105 0.335849 0.107546 0.27279 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 391 NME2 0.834631 1.124905 0.892405 1.066103 NA Retinopathy NA NA NA

392 NOD2 0.659464 1.79241 0.74016 1.493723 NA NA NA Nephropathy NA

393 NOS1 0.260742 1.183476 0.343217 0.972556 NA Retinopathy NA Nephropathy Neuropathy

394 NOS2 0.167925 1.79043 0.212736 1.265567 NA Retinopathy NA Nephropathy NA

395 NOS3 0.213642 1.300769 0.117296 0.847379 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 396 NOV 0.520241 1.625557 0.601274 1.402468 NA NA NA Nephropathy NA

397 NOX1 0.330106 1.038624 0.333831 0.845287 NA NA NA Nephropathy NA

398 NOX3 0.077616 0.434962 0.079063 0.319427 NA NA NA Nephropathy NA

399 NOX4 0.086914 1.206294 0.018602 0.758443 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 400 NPHS1 0.139063 0.975577 0.220944 0.883784 NA NA NA Nephropathy NA

401 NPPA 0.235241 1.292921 0.543735 1.233461 Cardiovascular NA NA NA NA diseases 402 NPY 0.410942 2.486584 0.524103 1.875884 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

403 NPY2R 0.138969 1.385377 0.255664 0.991305 Cardiovascular NA NA NA NA diseases 404 NPY5R 0.189438 2.177084 0.380118 1.748897 Cardiovascular NA NA NA NA diseases 405 NQO1 0.284593 0.929595 0.386527 0.813737 Cardiovascular NA Atherosclerosis NA NA diseases 406 NR1H3 0.644188 2.204277 0.896813 1.905149 NA NA NA Nephropathy NA

407 NR3C2 0.68027 1.287848 0.679312 1.12902 Cardiovascular NA NA NA NA diseases 408 NRF1 0.790636 1.608859 0.838858 1.521879 NA NA NA NA Neuropathy

409 NSA2 0.634965 1.195941 0.776313 1.10589 NA NA NA Nephropathy NA

410 NTF3 0.633254 1.424442 0.742739 1.387283 NA NA NA NA Neuropathy

110

411 NTS 0.085121 1.104058 0.214956 0.945401 Cardiovascular NA NA NA NA diseases 412 NUCB2 0.788001 2.617127 0.662873 1.902594 Cardiovascular Retinopathy NA NA NA diseases 413 ONECUT 0.56863 1.743248 0.785567 1.635431 NA NA NA Nephropathy NA 1 414 OSM 0.207535 1.510893 0.33594 1.134645 NA NA NA Nephropathy NA

415 OXT 0.073748 4.60661 0.209908 3.17803 Cardiovascular NA NA NA NA diseases 416 P2RX2 0.554072 1.778455 0.768957 1.554037 NA NA NA NA Neuropathy

417 P2RX3 0.210285 2.643725 0.613772 2.361985 NA NA NA NA Neuropathy

418 P2RY1 0.069531 1.412119 0.079824 1.188278 NA NA NA NA Neuropathy

419 P2RY2 0.224782 1.760596 0.380053 1.456228 NA NA NA NA Neuropathy

420 PAK6 0.257575 2.024274 0.385768 1.564631 NA NA NA NA Neuropathy

421 PARL 0.610783 1.864652 0.658013 1.672782 Cardiovascular NA NA Nephropathy NA diseases 422 PARP1 0.803842 1.213461 0.847801 1.131949 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 423 PC 0.724846 1.891966 0.869826 1.59597 NA NA NA Nephropathy NA

424 PCSK9 0.563368 1.441807 0.697897 1.266387 Cardiovascular NA Atherosclerosis NA NA diseases 425 PDE5A 0.298014 1.081552 0.4124 0.964484 NA NA NA Nephropathy Neuropathy

426 PDGFA 0.262105 2.070116 0.419585 1.653797 NA NA NA Nephropathy NA

427 PDGFB 0.359702 1.543695 0.404339 1.168184 NA NA NA Nephropathy NA

428 PDGFD 0.656876 1.67198 0.592745 1.345888 NA NA Atherosclerosis NA NA

429 PDGFRB 0.182093 2.030508 0.596236 1.868012 NA NA NA Nephropathy NA

430 PDHX 0.483338 1.294786 0.420922 1.101063 NA Retinopathy NA NA NA

431 PDK1 0.671044 1.260961 0.802939 1.241098 NA NA NA Nephropathy NA

432 PDPK1 0.714615 1.475892 0.701237 1.237599 NA NA NA Nephropathy NA

433 PEAR1 0.605379 1.400389 0.818696 1.337604 Cardiovascular NA NA NA NA diseases 434 PEBP1 0.777752 1.517011 0.91514 1.491421 NA NA NA Nephropathy NA

435 PECAM1 0.429462 1.703414 0.5551 1.313898 NA NA NA NA Neuropathy

436 PFKFB2 0.457266 1.048493 0.505813 0.897759 NA NA NA Nephropathy NA

437 PGF 0.554034 1.616191 0.698367 1.441575 Cardiovascular NA NA NA NA diseases 438 PHACTR1 0.206977 1.026522 0.250407 0.834709 Cardiovascular NA NA NA NA diseases 439 PICK1 0.951975 3.09234 0.851127 2.247941 NA NA NA Nephropathy NA

440 PIGF 0.632239 1.141437 0.743505 1.055815 NA Retinopathy NA NA NA

441 PIK3CA 0.480098 1.15418 0.660305 1.086967 NA NA NA Nephropathy NA

442 PIP 0.137667 1.959905 0.581327 1.799214 NA NA NA Nephropathy NA

443 PLA2G2A 0.287389 2.214259 0.629664 1.940428 NA NA Atherosclerosis NA NA

444 PLEKHH 0.714264 1.439148 0.690648 1.23349 NA NA NA Nephropathy NA 2 445 PLIN1 0.254172 2.80653 0.282718 2.180606 Cardiovascular NA NA NA NA diseases 446 PLIN2 0.558317 1.64581 0.861818 1.653562 Cardiovascular NA NA NA NA diseases 447 PLN 0.083962 1.578198 0.036128 1.031067 Cardiovascular NA NA NA NA diseases 448 PLTP 0.499393 1.120825 0.606751 1.044457 NA NA Atherosclerosis NA NA

449 PLXDC1 0.402818 1.315598 0.54954 1.16058 NA Retinopathy NA NA NA

450 PMP22 0.610516 1.203323 0.730464 1.101496 NA NA NA NA Neuropathy

451 PNPLA3 0.609135 2.010781 0.572738 1.627284 Cardiovascular NA NA NA NA diseases 452 POLR2D 0.732871 1.154687 0.797891 1.045327 NA Retinopathy NA NA NA

453 POMC 0.336337 3.253537 0.261739 2.149356 Cardiovascular NA NA NA Neuropathy diseases 454 PON1 0.864994 1.214581 0.876949 1.146617 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases

111

455 PON2 0.716501 1.552817 0.681531 1.262627 NA NA Atherosclerosis Nephropathy NA

456 PON3 0.757314 1.548258 0.801502 1.439163 Cardiovascular NA Atherosclerosis NA NA diseases 457 POSTN 0.207591 1.269252 0.537196 1.229937 NA Retinopathy NA Nephropathy NA

458 PPARA 0.774823 1.86316 0.805992 1.6457 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 459 PPARG 0.272741 1.486028 0.556743 1.362259 NA Retinopathy Atherosclerosis Nephropathy NA

460 PPARGC1 0.314417 3.014263 0.307924 2.038471 Cardiovascular Retinopathy NA Nephropathy Neuropathy A diseases 461 PPIA 0.760731 1.315306 0.805083 1.220796 Cardiovascular NA NA Nephropathy NA diseases 462 PPY 0.151112 1.755664 0.21082 1.676718 NA NA NA NA Neuropathy

463 PRCP 0.533598 0.903644 0.635267 0.910276 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 464 PRDX1 0.635199 1.490386 0.686084 1.284992 Cardiovascular NA NA NA NA diseases 465 PRDX2 0.771152 1.251014 0.803792 1.216578 Cardiovascular NA NA NA NA diseases 466 PRDX4 0.490022 1.223317 0.652628 1.092792 Cardiovascular NA NA NA NA diseases 467 PRDX6 0.733312 1.379117 0.870603 1.341559 Cardiovascular NA NA NA NA diseases 468 PRKAA1 0.323025 1.129105 0.442264 0.979568 NA NA NA Nephropathy NA

469 PRKCB 0.522692 1.068223 0.580159 0.950291 NA NA NA Nephropathy Neuropathy

470 PRKCE 0.2225 0.982477 0.347167 0.864052 NA NA NA Nephropathy NA

471 PRKG1 0.139063 1.053068 0.319597 0.959001 NA NA NA NA Neuropathy

472 PRMT2 0.911962 1.145807 0.924523 1.102242 NA NA Atherosclerosis NA NA

473 PROC 0.572867 1.341978 0.669197 1.284064 NA NA NA Nephropathy NA

474 PROM1 0.336088 1.686946 0.53679 1.454691 NA NA NA NA Neuropathy

475 PSIP1 0.62361 1.431972 0.676759 1.261715 NA Retinopathy NA NA NA

476 PSMA6 0.751757 1.146192 0.834775 1.114818 Cardiovascular NA NA Nephropathy NA diseases 477 PSMD9 0.781407 1.514164 0.840221 1.307464 NA Retinopathy NA Nephropathy Neuropathy

478 PTEN 0.623819 1.151814 0.718515 1.060231 NA NA NA Nephropathy Neuropathy

479 PTGDS 0.181014 1.734667 0.368437 1.343102 NA NA Atherosclerosis Nephropathy NA

480 PTGER1 0.225548 1.48566 0.121969 0.979048 NA NA NA Nephropathy NA

481 PTGER4 0.259758 0.471859 0.301959 0.455543 NA NA NA Nephropathy NA

482 PTGES 0.556759 1.548742 0.652688 1.422282 NA NA NA Nephropathy NA

483 PTGS2 0.332177 0.932047 0.295046 0.759974 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 484 PTH 0.036575 0.881604 0.044142 0.615367 Cardiovascular NA NA Nephropathy NA diseases 485 PTH1R 0.8509 1.759857 0.900891 1.595744 NA NA NA Nephropathy NA

486 PTPN1 0.597702 1.458493 0.550489 1.202102 Cardiovascular NA NA Nephropathy NA diseases 487 PTX3 0.232849 1.266539 0.212792 0.944765 NA Retinopathy Atherosclerosis Nephropathy NA

488 PVT1 0.412395 1.322315 0.531929 1.156697 NA NA NA Nephropathy NA

489 RAF1 0.655341 1.737081 0.83872 1.623142 NA Retinopathy NA Nephropathy NA

490 RARRES2 0.770703 1.343135 0.839424 1.279877 Cardiovascular NA NA NA NA diseases 491 RBP1 0.616786 1.716863 0.62861 1.48628 NA Retinopathy NA NA NA

492 RBP4 0.602599 1.35007 0.771811 1.314122 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 493 RCAN1 0.293868 1.275445 0.289482 0.927113 NA NA NA Nephropathy NA

494 REG1A 0.173828 2.789808 0.527508 2.403033 NA NA NA Nephropathy NA

495 RELA 0.666023 1.419653 0.783916 1.263021 NA Retinopathy NA Nephropathy NA

496 REN 0.184023 2.515961 0.028377 1.558321 Cardiovascular NA Atherosclerosis NA NA diseases 497 RETN 0.17781 1.592405 0.228058 1.319589 Cardiovascular NA Atherosclerosis NA NA diseases 498 RGN 0.536548 1.372174 0.627361 1.245671 NA NA NA Nephropathy NA

112

499 RHO 0.657471 2.433571 0.734205 1.996875 NA Retinopathy NA NA NA

500 RHOA 0.411196 1.456481 0.575893 1.274666 NA NA NA NA Neuropathy

501 RHOD 0.699647 2.483319 0.743937 2.002424 NA NA NA Nephropathy NA

502 RNLS 0.567829 1.523733 0.599192 1.273762 Cardiovascular NA NA NA NA diseases 503 ROCK1 0.554726 1.221241 0.593165 1.033293 NA NA NA Nephropathy NA

504 ROCK2 0.763738 1.765006 0.795885 1.475207 NA NA Atherosclerosis NA NA

505 ROMO1 1.018105 1.501885 1.013668 1.401472 NA Retinopathy NA NA NA

506 RPS12 0.565843 1.937041 0.703505 1.831639 NA NA NA Nephropathy NA

507 RPS6 0.74248 1.274777 0.732886 1.095203 NA NA NA Nephropathy NA

508 RPS6KA6 0.173828 0.857886 0.272995 0.686077 NA NA NA NA Neuropathy

509 RREB1 0.44679 1.533693 0.59305 1.251004 NA NA NA Nephropathy NA

510 RTN1 0.508735 1.874108 0.641339 1.749071 NA NA NA Nephropathy NA

511 S100A12 0.680732 1.567332 0.734376 1.300481 Cardiovascular Retinopathy NA NA NA diseases 512 SARDH 0.584655 1.310516 0.707959 1.2244 NA Retinopathy NA NA NA

513 SCAF1 0.37783 3.078779 0.238997 2.329986 NA NA Atherosclerosis NA NA

514 SCARB1 0.824343 1.865305 0.810549 1.49004 NA NA Atherosclerosis NA NA

515 SELE 0.221555 1.025146 0.4055 0.936461 NA NA NA Nephropathy NA

516 SEMA3A 0.093794 0.54923 0.099487 0.482651 NA NA NA Nephropathy NA

517 SERPINB 0.085577 0.213642 0.101185 0.193333 NA NA NA Nephropathy NA 7 518 SERPINE 0.372816 1.73339 0.447993 1.407208 NA NA NA Nephropathy NA 1 519 SERPINF 0.784612 1.299681 0.824748 1.217709 NA Retinopathy NA Nephropathy Neuropathy 1 520 SERPINF 0.803179 1.411934 0.926553 1.431898 NA NA NA Nephropathy NA 2 521 SETD7 0.492654 1.169814 0.530394 1.033935 Cardiovascular NA NA Nephropathy NA diseases 522 SFI1 0.508313 1.845883 0.708681 1.636814 NA NA NA Nephropathy NA

523 SGK1 0.586486 1.369663 0.606857 1.162436 NA NA NA Nephropathy NA

524 SGK2 0.602661 1.339705 0.689176 1.161514 NA NA NA Nephropathy NA

525 SGK3 0.818028 1.426986 0.801705 1.226647 NA NA NA Nephropathy NA

526 SHBG 0.164249 4.199035 0.413713 3.437968 Cardiovascular NA NA NA NA diseases 527 SIGLEC1 0.547157 1.95529 0.67798 1.647674 NA NA NA Nephropathy NA

528 SIRT1 0.577819 1.404903 0.557178 1.17961 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 529 SIRT6 0.717636 1.377462 0.85353 1.363552 NA NA NA Nephropathy NA

530 SLC12A3 0.119808 1.549105 0.067419 1.06305 NA NA NA Nephropathy NA

531 SLC22A6 0.304199 0.872885 0.247086 0.652491 NA NA NA Nephropathy NA

532 SLC2A1 0.285122 1.497677 0.419855 1.306689 Cardiovascular NA NA Nephropathy NA diseases 533 SLC2A2 0.630449 1.253726 0.692041 1.111712 NA NA NA Nephropathy NA

534 SLC2A3 0.547692 2.068555 0.36476 1.422916 NA NA NA NA Neuropathy

535 SLC2A4 0.103488 2.073887 0.369801 1.70341 Cardiovascular NA NA Nephropathy Neuropathy diseases 536 SLC30A10 0.580491 1.525351 0.581123 1.265451 NA NA NA NA Neuropathy

537 SLC30A8 0.404878 1.220924 0.51085 1.09954 NA NA NA Nephropathy NA

538 SLC5A2 0.726303 1.132999 0.738896 1.098916 Cardiovascular NA NA NA NA diseases 539 SLC9A1 0.601614 1.305095 0.688962 1.202761 NA NA NA Nephropathy NA

540 SLMAP 0.66692 1.245141 0.7285 1.179837 NA Retinopathy NA NA NA

541 SMAD1 0.511081 1.045478 0.630946 0.990355 NA NA NA Nephropathy NA

542 SMAD7 0.443548 1.110838 0.55637 1.021745 NA NA NA Nephropathy NA

113

543 SMG1 0.644858 1.231009 0.691084 1.13631 NA Retinopathy NA NA NA

544 SMPD1 0.286507 2.186873 0.455095 1.991117 NA Retinopathy NA NA NA

545 SOCS1 0.135533 0.856586 0.31338 0.754976 NA NA NA Nephropathy NA

546 SOCS2 0.283396 1.399244 0.34184 1.077716 NA NA NA Nephropathy NA

547 SOCS3 0.785577 1.42024 0.874754 1.384474 NA Retinopathy NA Nephropathy NA

548 SOD1 0.769266 1.300486 0.813057 1.188777 NA Retinopathy NA Nephropathy NA

549 SOD2 0.392576 1.182454 0.526484 1.153041 NA Retinopathy NA NA Neuropathy

550 SORBS2 0.755409 2.649408 0.726674 2.016687 NA NA NA Nephropathy NA

551 SOST 0.051346 1.564453 -0.0016 1.138032 Cardiovascular NA Atherosclerosis NA NA diseases 552 SOX9 0.243876 1.037514 0.466091 1.015504 NA NA NA Nephropathy NA

553 SPARC 0.681309 1.199574 0.808718 1.121661 NA Retinopathy NA Nephropathy NA

554 SPON2 0.821052 1.76554 0.945867 1.565348 NA NA NA Nephropathy NA

555 SPP1 0.138332 1.973628 0.150782 1.310569 Cardiovascular Retinopathy NA Nephropathy NA diseases 556 SRC 0.436502 1.07636 0.520042 0.97266 NA NA NA Nephropathy NA

557 SREBF1 0.681708 1.964877 0.646315 1.57503 NA NA NA Nephropathy Neuropathy

558 SRGN 0.44958 1.295904 0.487525 1.018439 NA Retinopathy NA NA NA

559 SST 0.256731 1.773047 0.24046 1.465929 NA Retinopathy NA Nephropathy NA

560 STAT1 0.656316 2.197859 0.544677 1.565761 NA NA NA Nephropathy NA

561 STAT3 0.851825 1.427867 0.873404 1.295169 NA Retinopathy NA Nephropathy NA

562 STAT5A 0.748712 1.279064 0.803957 1.235691 NA NA NA Nephropathy NA

563 STEAP4 0.279475 1.00434 0.354859 0.957162 NA NA Atherosclerosis NA NA

564 STH 0.310194 1.286875 0.605297 1.320124 NA NA NA Nephropathy NA

565 STK11 0.471096 1.415772 0.610406 1.347217 NA NA NA Nephropathy NA

566 SUCNR1 0.490274 1.864805 0.440827 1.396937 NA NA NA Nephropathy NA

567 SUMO4 0.848146 0.978094 0.883267 0.962005 Cardiovascular NA NA Nephropathy NA diseases 568 SYVN1 0.893546 1.7216 0.914177 1.489995 NA Retinopathy NA NA NA

569 TACR1 0.365753 0.737355 0.406266 0.678056 Cardiovascular NA NA NA NA diseases 570 TCF7L2 0.652093 1.130995 0.759192 1.036036 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 571 TF 0.662138 1.469343 0.809203 1.412511 NA NA NA Nephropathy NA

572 TFAM 0.503761 1.158292 0.713965 1.151337 NA NA NA NA Neuropathy

573 TGFB1 0.267096 1.471609 0.444581 1.174869 Cardiovascular NA NA Nephropathy NA diseases 574 TGFBR1 0.556594 1.098947 0.617509 1.008933 NA NA NA Nephropathy NA

575 TH 0.103488 1.23797 0.399231 1.186582 NA Retinopathy NA NA Neuropathy

576 THBD 0.249906 2.129722 0.390393 1.612382 NA NA NA Nephropathy NA

577 THBS1 0.260539 1.338346 0.463288 1.159411 NA Retinopathy NA Nephropathy NA

578 THBS2 0.676027 1.966402 0.651159 1.570516 NA NA NA Nephropathy NA

579 TIMM44 0.735295 1.813074 0.857473 1.62581 NA NA NA Nephropathy NA

580 TIMP1 0.532593 3.110203 0.164837 1.992704 NA Retinopathy NA NA NA

581 TIMP2 0.48452 1.102218 0.600887 1.042928 NA NA NA Nephropathy NA

582 TIMP3 0.660859 1.260501 0.764955 1.155228 NA Retinopathy Atherosclerosis Nephropathy NA

583 TKT 0.397351 1.414442 0.700124 1.385744 NA NA NA Nephropathy Neuropathy

584 TLR2 0.839054 1.10858 0.839037 1.04857 NA NA NA Nephropathy NA

585 TLR4 0.544254 1.237844 0.590927 1.137927 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

586 TM6SF2 0.839696 1.397331 0.804308 1.238463 Cardiovascular NA NA NA NA diseases

114

587 TNF 0.432905 1.431865 0.609326 1.358431 NA Retinopathy NA Nephropathy Neuropathy

588 TNFAIP8 0.318026 1.105616 0.429142 1.037737 NA NA NA Nephropathy NA

589 TNFRSF1 0.764183 1.246485 0.752101 1.087679 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy 1B diseases 590 TNFRSF1 0.924159 1.61853 0.890053 1.504909 NA NA NA NA Neuropathy B 591 TPM1 0.675943 1.359795 0.753256 1.172659 Cardiovascular NA NA NA NA diseases 592 TRAF6 0.431293 1.534483 0.650351 1.357567 NA NA NA NA Neuropathy

593 TRH 0.293868 2.051172 0.136444 1.35727 NA NA NA NA Neuropathy

594 TRIB3 0.46786 1.832834 0.500456 1.467527 Cardiovascular NA NA Nephropathy NA diseases 595 TRPA1 0.239425 1.124751 0.337854 0.935199 NA NA NA NA Neuropathy

596 TRPC1 0.20094 0.979954 0.313407 0.989789 NA NA NA Nephropathy NA

597 TRPC6 0.077616 0.915673 0.139147 0.712027 NA NA Atherosclerosis Nephropathy NA

598 TRPV1 0.779829 1.831524 0.982842 1.650583 NA NA NA NA Neuropathy

599 TRPV3 0.736272 1.563041 0.797314 1.303483 NA NA NA NA Neuropathy

600 TRPV4 0.252712 1.963207 0.449033 1.572555 NA NA NA Nephropathy NA

601 TSC1 0.746087 1.616998 0.789022 1.489433 NA NA NA Nephropathy NA

602 TSC2 0.691499 3.203916 0.775185 2.542186 NA NA NA Nephropathy NA

603 TSC22D1 0.295508 0.853779 0.358807 0.7961 NA NA NA Nephropathy NA

604 TSPO 0.639668 1.426002 0.797441 1.327298 NA NA NA NA Neuropathy

605 TUBB3 0.620947 2.500906 0.506484 1.930766 NA Retinopathy NA NA NA

606 TXN 0.714869 1.190036 0.790914 1.105289 Cardiovascular NA Atherosclerosis NA NA diseases 607 TXNIP 0.696637 1.362193 0.677664 1.210323 NA Retinopathy Atherosclerosis Nephropathy NA

608 UCP1 0.184023 2.561337 -0.28314 1.433478 NA Retinopathy NA NA NA

609 UCP2 0.76117 1.469316 0.743415 1.194175 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

610 UHRF1 0.104215 1.888663 -0.13298 1.116179 NA NA NA Nephropathy NA

611 UMOD 0.225977 2.225 0.150025 1.673188 NA NA NA Nephropathy NA

612 UNC13A 0.601796 1.462045 0.660135 1.218687 NA NA NA NA Neuropathy

613 UNC13B 0.968259 1.878652 0.962081 1.63158 NA NA NA Nephropathy NA

614 UNC5B 0.87793 1.027133 0.907544 1.024331 NA NA NA Nephropathy NA

615 USF2 0.92174 1.404493 1.015836 1.332982 NA NA NA Nephropathy NA

616 UTRN 0.741279 1.276278 0.819542 1.215427 NA NA NA Nephropathy NA

617 UTS2 0.304693 1.451065 0.539967 1.265512 NA Retinopathy Atherosclerosis NA NA

618 UTS2R 0.250979 1.818713 0.449901 1.527372 NA NA NA Nephropathy NA

619 VCAM1 0.23141 1.159964 0.283571 0.992179 Cardiovascular NA Atherosclerosis NA NA diseases 620 VDAC1 0.446899 1.518087 0.594933 1.359395 NA NA NA Nephropathy NA

621 VDAC2 0.490407 1.375815 0.629961 1.205432 NA NA NA Nephropathy NA

622 VDR 0.790543 1.289654 0.848055 1.264181 Cardiovascular Retinopathy NA Nephropathy NA diseases 623 VEGFA 0.720753 1.311471 0.76603 1.228924 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

624 VEGFC 0.497787 1.034809 0.593838 0.960325 NA Retinopathy NA NA NA

625 VIP 0.16507 1.380407 0.416923 1.298123 NA NA NA NA Neuropathy

626 VWF 0.405995 1.428523 0.3668 1.096974 Cardiovascular NA NA Nephropathy Neuropathy diseases 627 WFS1 0.652646 2.365627 0.708385 1.949229 NA NA NA Nephropathy NA

628 WT1 0.301128 1.206957 0.338024 1.00499 NA NA NA Nephropathy NA

629 XBP1 0.723894 1.288232 0.782539 1.166072 NA NA NA Nephropathy NA

630 XIAP 0.629866 1.196518 0.799378 1.194461 NA NA NA NA Neuropathy

115

631 XRCC1 0.717215 1.370118 0.750007 1.239413 Cardiovascular Retinopathy NA NA NA diseases 632 ZEB2 0.457278 1.132199 0.559855 1.025515 NA NA NA Nephropathy NA

633 ZNF236 0.523648 1.418159 0.686896 1.213727 NA NA NA Nephropathy NA

634 ZNRF1 0.561547 1.49761 0.734146 1.340147 NA Retinopathy NA NA NA

Table A.5: table for muscle tissue

Genes Actual Actual 99% CI 99% CI complication1 complication2 complication3 complication4 complication5 Min Max Min Max 1 ABCA1 4.644681 5.71338 4.972853 5.180895 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 2 ABCG1 4.028118 6.203263 5.182863 5.540547 Cardiovascular NA Atherosclerosi NA NA diseases s 3 ABO 5.887288 7.355846 6.348945 6.656827 Cardiovascular NA NA NA NA diseases 4 ACACB 7.179278 8.148579 7.550989 7.723974 NA NA NA Nephropathy NA

5 ACAT1 3.111058 4.055755 3.504179 3.645473 NA NA Atherosclerosi NA NA s 6 ACE 4.193106 5.354773 4.78544 4.957371 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 7 ACSL1 9.230631 11.01283 9.902912 10.20619 NA NA Atherosclerosi NA NA s 8 ACVRL1 5.565816 6.88524 6.108994 6.341058 NA NA NA Nephropathy NA

9 ADAM10 6.884963 8.021707 7.451198 7.635908 NA NA NA Nephropathy NA

10 ADAM17 6.334213 7.773016 6.965358 7.147259 NA NA Atherosclerosi Nephropathy NA s 11 ADCYAP 5.663905 7.064476 6.205611 6.428121 NA Retinopathy NA Nephropathy NA 1 12 ADH1B 5.86059 8.57197 7.152318 7.525183 NA NA NA Nephropathy Neuropathy

13 ADIPOQ 6.44082 8.373359 7.026706 7.272532 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 14 ADK 7.015776 7.927847 7.327482 7.500381 NA Retinopathy NA NA NA

15 ADM 7.027474 9.961346 8.640544 9.114657 NA Retinopathy NA Nephropathy Neuropathy

16 AGER 4.494796 6.076105 5.11131 5.373832 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 17 AGT 6.569985 8.274629 7.232305 7.500863 NA NA NA Nephropathy Neuropathy

18 AGTR1 5.353474 7.833996 6.419374 6.762894 NA NA NA Nephropathy NA

19 AHSA1 8.161186 9.280975 8.778848 8.952166 Cardiovascular Retinopathy NA Nephropathy NA diseases 20 AHSG 5.664378 6.365949 5.992452 6.116745 Cardiovascular Retinopathy NA Nephropathy NA diseases 21 AKR1B1 10.31458 11.30009 10.82034 10.99116 NA Retinopathy NA Nephropathy Neuropathy

22 AKR1B10 5.487744 7.022595 5.970472 6.23495 NA NA NA Nephropathy NA

23 AKT1 6.496571 8.253868 7.345734 7.62621 Cardiovascular Retinopathy NA Nephropathy NA diseases 24 ALB 3.094387 4.744576 3.692412 4.001112 NA NA Atherosclerosi Nephropathy Neuropathy s 25 ALDH1A 7.905918 9.674537 8.596726 8.979144 NA NA NA Nephropathy NA 1 26 ALDH2 9.55236 10.62268 9.988208 10.21887 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 27 ALOX5A 5.624408 6.659334 6.065193 6.25544 NA NA Atherosclerosi Nephropathy NA P s 28 ALPL 4.661512 7.314767 5.522648 5.954928 NA NA NA Nephropathy NA

29 AMBP 5.251317 6.593607 5.874311 6.153114 NA NA NA Nephropathy NA

30 ANG 5.884059 7.095466 6.415062 6.651954 NA NA NA Nephropathy NA

31 ANGPT2 4.705894 5.547668 4.956756 5.117332 NA Retinopathy NA NA NA

32 ANGPTL 7.764014 10.16853 8.622032 8.975221 NA NA Atherosclerosi Nephropathy NA 2 s 33 AOC2 5.20133 6.296483 5.726608 5.942218 NA NA NA Nephropathy NA

34 AOC3 6.042314 7.593149 6.515192 6.764149 NA Retinopathy NA NA NA

35 APC 6.597944 7.848011 7.292353 7.509639 NA NA NA Nephropathy NA

116

36 API5 6.157899 7.20411 6.459287 6.626553 NA Retinopathy NA NA NA

37 APLNR 6.520054 7.666997 6.970676 7.162743 NA NA NA Nephropathy NA

38 APOA1 5.314985 6.572817 5.795244 6.019855 Cardiovascular Retinopathy Atherosclerosi NA NA diseases s 39 APOB 5.058913 5.997138 5.379012 5.550897 Cardiovascular Retinopathy NA NA Neuropathy diseases 40 APOC1 6.252204 8.129447 6.735655 7.061704 NA NA NA Nephropathy NA

41 APOC3 5.108207 6.424385 5.595837 5.814326 Cardiovascular NA NA Nephropathy NA diseases 42 APOE 5.668774 8.195815 6.426785 6.857245 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 43 APOH 4.466243 5.478084 4.829287 4.982814 Cardiovascular NA NA NA NA diseases 44 APOL1 6.660299 7.855593 7.205983 7.424265 Cardiovascular NA NA Nephropathy NA diseases 45 APOM 6.230401 7.022489 6.456944 6.575404 NA NA Atherosclerosi NA NA s 46 AQP1 6.949923 9.431804 7.87567 8.256344 NA Retinopathy NA NA NA

47 AQP4 3.590284 5.742907 4.526307 4.90893 NA Retinopathy NA NA NA

48 AQP5 6.399532 7.593974 6.72087 6.913316 NA NA NA Nephropathy NA

49 AR 6.18892 8.180699 7.214535 7.522378 NA NA NA Nephropathy NA

50 ASPA 5.639231 7.410979 6.285057 6.541672 NA NA NA NA Neuropathy

51 ATF4 10.49741 11.43728 10.95153 11.11283 NA Retinopathy NA Nephropathy NA

52 ATM 5.152113 6.544371 5.813671 6.056759 Cardiovascular NA NA NA NA diseases 53 ATP2A2 6.600917 7.975446 7.114852 7.343575 NA NA NA NA Neuropathy

54 B2M 11.34096 12.99997 12.34273 12.54836 NA NA Atherosclerosi Nephropathy NA s 55 BAAT 5.394243 6.355594 5.799762 5.97308 NA NA Atherosclerosi NA NA s 56 BAMBI 6.016737 7.828924 6.526038 6.752203 NA NA NA Nephropathy NA

57 BASP1 7.05036 8.621273 7.593693 7.835947 NA NA NA Nephropathy NA

58 BCL2 6.347196 6.856995 6.473266 6.562747 NA NA NA Nephropathy NA

59 BDKRB1 5.163897 7.700608 6.123683 6.537823 NA NA NA NA Neuropathy

60 BDKRB2 6.511363 8.118005 7.139395 7.426781 NA NA NA NA Neuropathy

61 BDNF 5.322232 6.993553 5.948317 6.201794 NA Retinopathy NA NA Neuropathy

62 BMP2 3.754994 5.932734 4.34054 4.746598 NA NA Atherosclerosi NA NA s 63 BMP4 5.725247 7.030233 6.351971 6.579586 NA NA NA Nephropathy NA

64 BNIP3 8.403498 10.28615 9.075983 9.422009 Cardiovascular NA NA NA NA diseases 65 C5 5.578452 7.232501 6.064572 6.358337 NA Retinopathy NA Nephropathy NA

66 CACNA1 5.904669 6.918248 6.341971 6.531634 NA NA NA NA Neuropathy H 67 CAT 8.814892 10.61034 9.713541 9.980117 NA Retinopathy NA Nephropathy NA

68 CAV1 8.933924 11.09948 10.14082 10.44883 NA NA NA Nephropathy Neuropathy

69 CCK 4.514499 5.713938 4.929195 5.140025 NA NA NA Nephropathy Neuropathy

70 CCKAR 6.679327 7.671532 6.992417 7.15081 NA NA NA Nephropathy NA

71 CCL2 6.311206 9.65348 7.376271 7.891767 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 72 CCL20 4.415872 7.91697 5.206085 5.691258 NA NA NA Nephropathy NA

73 CCL5 4.777051 6.618283 5.516397 5.842191 NA NA NA Nephropathy NA

74 CCR1 3.976278 5.984149 4.906595 5.201076 NA NA NA Nephropathy NA

75 CCR2 4.218287 5.754521 4.919705 5.191812 NA NA Atherosclerosi Nephropathy NA s 76 CCR5 5.843805 6.990937 6.258506 6.473159 NA NA Atherosclerosi Nephropathy NA s 77 CD160 3.599492 5.054449 4.233438 4.471172 NA Retinopathy NA NA NA

78 CD163 5.100689 5.896379 5.417377 5.557804 NA Retinopathy Atherosclerosi NA Neuropathy s 79 CD247 4.0205 5.187223 4.540179 4.750577 Cardiovascular NA NA NA NA diseases

117

80 CD2AP 5.688783 7.43268 6.665574 6.958492 NA NA NA Nephropathy NA

81 CD34 6.629232 8.108624 7.196964 7.384422 NA NA NA NA Neuropathy

82 CD36 6.875772 9.805063 8.105871 8.529413 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 83 CD38 5.913229 6.766947 6.195615 6.356992 NA NA NA Nephropathy NA

84 CD4 6.825248 8.326609 7.363064 7.607084 Cardiovascular NA Atherosclerosi NA NA diseases s 85 CD40 5.232848 6.418426 5.629118 5.830388 Cardiovascular NA Atherosclerosi NA NA diseases s 86 CD40LG 5.394263 5.970303 5.655777 5.765591 Cardiovascular NA NA Nephropathy NA diseases 87 CD47 6.32978 7.230981 6.700397 6.853584 NA NA NA Nephropathy NA

88 CD59 9.87954 11.50156 10.37577 10.60974 NA Retinopathy NA NA NA

89 CD63 10.5557 11.7054 11.11159 11.2979 NA NA NA Nephropathy NA

90 CD68 5.89164 7.013678 6.394064 6.608756 NA NA NA Nephropathy NA

91 CD69 3.081317 3.852034 3.332191 3.459372 NA NA NA Nephropathy NA

92 CD74 5.118601 7.31159 5.72744 6.101852 NA NA NA Nephropathy NA

93 CD80 4.049657 5.749536 4.947128 5.230086 NA NA NA Nephropathy NA

94 CD9 6.858371 9.007885 7.88356 8.299438 Cardiovascular NA NA NA NA diseases 95 CDC123 7.483131 8.450648 8.022514 8.169106 Cardiovascular NA NA NA NA diseases 96 CDH1 5.076406 5.819785 5.408699 5.535931 NA NA NA Nephropathy NA

97 CDH2 4.122929 6.404837 5.382812 5.710902 NA NA NA Nephropathy NA

98 CDK7 6.467334 7.848383 7.068308 7.257636 NA NA NA Nephropathy NA

99 CDKN1A 8.824698 9.975761 9.32339 9.533019 NA NA NA Nephropathy NA

100 CDKN2A 4.281391 6.95904 4.900741 5.354028 Cardiovascular NA NA NA NA diseases 101 CETP 4.841533 6.404213 5.451581 5.651671 Cardiovascular NA Atherosclerosi NA NA diseases s 102 CHI3L1 4.844204 9.656166 6.478554 7.268041 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 103 CHIT1 5.446521 6.75802 5.9549 6.194781 NA NA NA Nephropathy NA

104 CHN2 6.187957 6.853312 6.448059 6.586948 NA Retinopathy NA Nephropathy NA

105 CITED2 6.731829 8.895097 7.731914 8.187592 NA NA Atherosclerosi NA NA s 106 CLCN5 3.802296 7.004252 5.181537 5.763367 NA NA NA Nephropathy NA

107 CLEC11 6.013674 7.135898 6.51158 6.727649 NA NA NA Nephropathy NA A 108 CLOCK 6.583979 8.57893 7.419278 7.695374 Cardiovascular NA NA NA NA diseases 109 CMA1 4.754724 7.051911 5.729651 6.114623 NA NA NA Nephropathy NA

110 CMC4 7.355107 8.279063 7.855398 8.008557 NA NA NA Nephropathy NA

111 CNR1 3.196038 4.433733 3.542464 3.727157 NA Retinopathy NA Nephropathy Neuropathy

112 CNR2 6.062311 7.095044 6.533452 6.735757 NA NA NA Nephropathy Neuropathy

113 CNTF 4.57984 5.598808 5.025119 5.241363 NA NA NA NA Neuropathy

114 COG2 7.056094 8.136981 7.467387 7.662758 NA NA Atherosclerosi NA NA s 115 COL8A1 3.586463 6.484891 4.885989 5.392394 NA NA NA Nephropathy NA

116 COMT 6.482352 7.650129 7.005594 7.241639 Cardiovascular NA NA NA NA diseases 117 CPVL 4.999874 6.209157 5.50667 5.718094 NA NA NA Nephropathy NA

118 CRH 5.794204 6.357528 6.021417 6.131921 NA NA NA NA Neuropathy

119 CRK 7.314602 8.227892 7.723832 7.88555 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 120 CRP 5.062309 5.906172 5.406664 5.571694 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 121 CST3 8.572444 10.55926 9.301219 9.650591 Cardiovascular NA NA NA NA diseases 122 CTGF 6.651758 9.153414 8.016803 8.46499 NA Retinopathy NA Nephropathy NA

123 CTSH 6.732647 9.731507 7.597774 8.103058 NA Retinopathy NA NA NA

118

124 CTSS 3.155765 5.758691 4.209079 4.606089 Cardiovascular NA NA NA NA diseases 125 CUBN 5.096202 6.090915 5.453775 5.633573 NA NA NA Nephropathy NA

126 CX3CL1 5.938377 6.675192 6.223513 6.362129 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 127 CX3CR1 4.465029 5.410556 4.902293 5.087471 NA NA NA Nephropathy NA

128 CXCL10 5.325997 7.061811 5.928768 6.176809 NA NA NA Nephropathy Neuropathy

129 CXCL11 2.634431 4.049819 3.01847 3.218706 NA NA NA Nephropathy NA

130 CXCL12 7.101299 9.547094 8.274454 8.683546 NA NA NA Nephropathy NA

131 CXCL5 2.942788 3.61264 3.200332 3.315761 NA NA Atherosclerosi Nephropathy NA s 132 CXCL8 3.949018 9.742529 5.774677 6.60563 NA NA NA Nephropathy NA

133 CXCL9 5.417997 6.746854 5.806244 6.048083 NA NA NA Nephropathy NA

134 CYBA 7.197236 8.925226 8.05977 8.31902 NA NA Atherosclerosi Nephropathy NA s 135 CYBB 5.330623 6.357042 5.796791 5.954174 NA Retinopathy NA NA NA

136 CYP1A1 6.043827 7.570445 6.418618 6.634172 Cardiovascular NA Atherosclerosi NA NA diseases s 137 CYP24A1 2.866103 4.561889 3.397833 3.713979 NA NA NA Nephropathy NA

138 CYP2C19 3.689128 4.965712 4.145988 4.365157 NA Retinopathy NA NA NA

139 CYP2J2 5.909943 7.849445 6.626668 6.9805 Cardiovascular NA NA Nephropathy NA diseases 140 CYP7A1 2.627348 4.647351 3.195997 3.575271 Cardiovascular NA NA NA NA diseases 141 CYR61 7.92708 9.651126 8.327996 8.617798 NA Retinopathy NA NA NA

142 DDAH1 4.926198 7.237696 5.489233 5.801132 NA Retinopathy NA Nephropathy NA

143 DDIT3 8.254364 9.614555 8.730638 8.991064 Cardiovascular NA NA Nephropathy Neuropathy diseases 144 DEFA1 5.519905 6.743292 5.89044 6.084246 NA NA NA Nephropathy NA

145 DES 9.137071 11.92413 10.0015 10.51089 NA NA NA Nephropathy NA

146 DHCR7 6.275597 7.798345 7.037262 7.295713 NA NA Atherosclerosi NA NA s 147 DKK1 5.660553 8.918868 6.643668 7.264506 Cardiovascular Retinopathy NA Nephropathy NA diseases 148 DNMT1 5.965649 7.713578 6.721591 6.964113 NA NA NA Nephropathy NA

149 DPP4 6.577458 8.891208 7.380508 7.778065 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 150 EDNRA 3.680289 6.181813 4.389823 4.818988 NA NA NA Nephropathy NA

151 EGF 5.777751 9.203505 6.91187 7.326994 NA NA NA Nephropathy NA

152 EGFR 5.17922 8.312508 6.468735 6.993075 Cardiovascular NA NA Nephropathy NA diseases 153 EIF4EBP 7.325476 9.06419 7.94321 8.222176 NA NA NA Nephropathy NA 1 154 ELMO1 5.091117 6.513946 5.648494 5.912079 NA NA NA Nephropathy NA

155 ELN 6.565444 8.476138 7.469209 7.769035 NA NA Atherosclerosi NA NA s 156 ENG 6.451791 8.177203 7.091025 7.392836 Cardiovascular Retinopathy NA NA Neuropathy diseases 157 ENPP1 3.586826 5.008478 3.968308 4.221011 NA NA NA Nephropathy NA

158 ENPP2 4.984995 9.032628 6.821799 7.491236 NA NA NA NA Neuropathy

159 ENTPD1 4.939712 5.63486 5.187336 5.306723 NA NA Atherosclerosi Nephropathy NA s 160 EPO 5.770281 6.591719 6.083631 6.232305 NA Retinopathy NA Nephropathy Neuropathy

161 EPOR 5.981589 6.87039 6.379563 6.564397 NA NA NA Nephropathy NA

162 ERBB2 4.106475 6.386311 5.081455 5.397694 Cardiovascular NA NA NA Neuropathy diseases 163 ERBB3 5.206093 6.476642 5.622091 5.844775 NA Retinopathy NA NA NA

164 ERBB4 4.542126 5.404519 5.023669 5.173377 NA NA NA Nephropathy NA

165 ERCC1 7.876571 9.164315 8.235194 8.429778 NA Retinopathy NA Nephropathy NA

166 ERCC4 5.773241 6.691548 6.208183 6.396093 NA Retinopathy NA Nephropathy NA

167 ESM1 2.787629 5.754052 3.880417 4.292081 NA NA NA NA Neuropathy

119

168 ESR1 5.691199 6.807998 6.023182 6.22392 NA NA NA Nephropathy NA

169 EXOSC7 7.635529 8.759419 8.075123 8.259648 NA NA NA Nephropathy NA

170 EZR 5.770159 8.125207 6.764521 7.189817 NA NA NA Nephropathy NA

171 F11 3.19363 4.794648 3.703093 3.944751 NA NA NA Nephropathy NA

172 F2R 6.458284 7.779894 6.965119 7.182132 NA NA NA Nephropathy NA

173 F8 7.055552 8.129859 7.592831 7.780802 NA NA NA NA Neuropathy

174 FABP1 2.992298 4.026337 3.319795 3.478407 Cardiovascular NA NA Nephropathy NA diseases 175 FABP2 5.713199 6.611968 6.051285 6.219291 NA NA NA Nephropathy NA

176 FABP4 6.933836 8.888703 7.514342 7.810866 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 177 FABP5 6.783566 9.005157 8.038731 8.385617 Cardiovascular NA Atherosclerosi NA NA diseases s 178 FADS1 5.624 7.525286 6.293867 6.612047 Cardiovascular NA NA NA NA diseases 179 FADS2 6.776872 7.875382 7.071316 7.263542 Cardiovascular NA NA NA NA diseases 180 FASN 7.20144 8.309471 7.615593 7.816306 NA NA NA Nephropathy NA

181 FGFR1 5.62982 7.212024 6.166041 6.477763 NA NA Atherosclerosi NA NA s 182 FKBP2 7.628435 8.577476 7.980704 8.145858 NA NA Atherosclerosi NA NA s 183 FKBP4 4.952709 6.167964 5.557075 5.752997 Cardiovascular NA NA NA NA diseases 184 FKBP8 6.896089 8.108024 7.412472 7.600992 Cardiovascular NA NA NA NA diseases 185 FMO3 4.734943 6.640764 5.546099 5.884721 NA NA Atherosclerosi NA NA s 186 FMOD 6.427602 7.974464 6.85251 7.118482 NA NA Atherosclerosi NA NA s 187 FOLH1 2.746367 4.107734 3.277787 3.489869 NA NA NA NA Neuropathy

188 FOS 4.81514 6.599894 5.51133 5.829572 NA NA NA Nephropathy NA

189 FOXA2 5.343046 6.290276 5.648635 5.814329 NA NA Atherosclerosi NA NA s 190 FOXO1 6.497087 7.881011 7.139533 7.396824 NA NA Atherosclerosi NA NA s 191 FOXO4 6.505581 7.326856 6.839601 6.999739 NA NA NA Nephropathy NA

192 FPR1 4.793679 6.149915 5.424226 5.679946 NA NA Atherosclerosi NA NA s 193 FTO 9.064173 9.764215 9.29344 9.429245 Cardiovascular NA NA Nephropathy NA diseases 194 G6PD 5.074388 6.618771 5.741111 6.027679 Cardiovascular NA NA Nephropathy Neuropathy diseases 195 GAP43 3.405747 4.628652 3.883069 4.112639 NA NA NA NA Neuropathy

196 GAPDH 13.38946 13.97095 13.62063 13.721 NA Retinopathy NA NA Neuropathy

197 GAS1 4.90288 7.855032 5.907313 6.276396 NA NA NA Nephropathy NA

198 GAS6 8.441732 10.66342 9.640916 9.940232 NA NA NA Nephropathy NA

199 GCG 3.345953 4.315392 3.715016 3.889172 NA NA NA Nephropathy NA

200 GCK 5.911116 6.739415 6.193913 6.34403 NA NA NA Nephropathy Neuropathy

201 GCKR 6.154278 6.737473 6.427306 6.534813 Cardiovascular NA NA NA NA diseases 202 GDF15 5.268744 6.414026 5.884481 6.088024 Cardiovascular NA NA Nephropathy NA diseases 203 GFAP 5.892713 6.661526 6.228555 6.356419 NA NA NA NA Neuropathy

204 GFPT1 7.239988 8.04772 7.545792 7.70658 NA NA NA Nephropathy NA

205 GFPT2 7.740135 9.024616 8.16324 8.412864 NA NA NA Nephropathy NA

206 GGT1 5.632692 6.560862 6.033532 6.20486 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 207 GHR 6.330428 8.61101 7.775636 8.120443 NA NA NA Nephropathy NA

208 GIP 4.870676 7.015905 5.888602 6.26604 Cardiovascular NA Atherosclerosi NA Neuropathy diseases s 209 GIPR 5.208287 6.320193 5.643865 5.836964 NA Retinopathy NA NA Neuropathy

210 GK 3.589909 4.698383 4.013577 4.163984 Cardiovascular NA NA NA NA diseases 211 GLO1 9.51094 10.52592 10.13376 10.30345 NA NA Atherosclerosi Nephropathy Neuropathy s

120

212 GLP1R 7.246203 7.852024 7.432018 7.526149 Cardiovascular NA NA NA Neuropathy diseases 213 GLUL 7.963973 10.16591 8.679122 9.125033 Cardiovascular NA NA NA NA diseases 214 GNB3 6.352568 7.245075 6.67509 6.855934 NA NA NA Nephropathy NA

215 GPC5 3.423348 4.290149 3.657871 3.845306 NA NA NA Nephropathy NA

216 GPX1 9.58734 10.45819 9.898414 10.06661 Cardiovascular Retinopathy Atherosclerosi NA NA diseases s 217 GRB2 7.129931 8.645961 7.643829 7.889633 NA Retinopathy NA NA NA

218 GREM1 6.125499 9.017947 7.237962 7.763576 NA NA NA Nephropathy NA

219 GSTM1 8.281627 9.986193 8.803087 9.123529 NA Retinopathy Atherosclerosi Nephropathy NA s 220 GSTT1 6.764805 9.281838 7.917136 8.334408 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 221 GYS1 8.282314 10.26628 9.135667 9.434651 Cardiovascular NA NA NA NA diseases 222 HCN2 3.924266 6.235509 4.822081 5.194648 NA NA NA NA Neuropathy

223 HDAC4 5.723873 6.565438 6.015556 6.156542 NA NA NA Nephropathy NA

224 HDAC9 5.500293 6.424556 5.865376 6.027722 NA NA Atherosclerosi NA NA s 225 HFE 4.369738 5.770142 5.048528 5.23075 NA Retinopathy NA Nephropathy NA

226 HGF 2.971723 4.894882 3.623876 3.945462 NA NA Atherosclerosi Nephropathy Neuropathy s 227 HHEX 4.777463 5.708666 5.204162 5.371261 Cardiovascular NA NA Nephropathy NA diseases 228 HIF1A 8.407375 9.464149 8.802821 9.001219 Cardiovascular NA NA Nephropathy NA diseases 229 HLA-A 9.989651 11.26329 10.58779 10.78747 NA NA NA Nephropathy NA

230 HLA- 6.039729 6.920992 6.276656 6.405102 NA NA NA Nephropathy NA DQA1 231 HMGA2 3.914099 6.48556 4.800638 5.242358 NA NA NA Nephropathy NA

232 HMGB1 8.622514 9.676106 8.973517 9.182945 Cardiovascular Retinopathy NA Nephropathy NA diseases 233 HMGCS2 5.217897 6.919007 6.015344 6.290561 NA NA NA Nephropathy NA

234 HMOX1 6.492717 9.596872 7.889868 8.471553 NA NA NA Nephropathy NA

235 HNF1A 6.293847 7.210655 6.582522 6.764237 NA NA NA Nephropathy NA

236 HNF1B 7.250134 8.09045 7.541351 7.712883 Cardiovascular NA NA NA NA diseases 237 HNF4A 5.702371 6.896832 6.095523 6.295866 Cardiovascular NA NA NA NA diseases 238 HP 5.328438 6.870084 5.8895 6.173994 Cardiovascular NA Atherosclerosi NA NA diseases s 239 HRH1 5.06429 6.568156 5.528535 5.811678 NA NA NA NA Neuropathy

240 HSPA1A 9.289665 11.08217 10.08064 10.41542 NA NA NA Nephropathy NA

241 HSPA1B 6.602642 8.558891 7.64758 7.996298 NA NA NA Nephropathy NA

242 HSPA5 9.211364 10.17231 9.706457 9.872941 NA NA NA NA Neuropathy

243 HSPB1 10.55916 12.41459 11.72181 11.98628 NA NA NA Nephropathy NA

244 HSPG2 6.081837 7.537042 6.695959 6.920965 NA NA NA Nephropathy NA

245 HTR2A 4.282572 6.314451 5.220374 5.572314 NA NA NA Nephropathy NA

246 HYOU1 6.98434 8.993937 7.875754 8.190506 NA NA NA Nephropathy Neuropathy

247 ICAM1 6.560985 8.520976 7.193191 7.52581 NA NA Atherosclerosi Nephropathy NA s 248 ID1 5.471282 10.26057 7.222404 8.042036 NA NA NA Nephropathy NA

249 IFNG 4.307714 5.671183 4.829001 5.095649 NA NA NA Nephropathy Neuropathy

250 IGF1 5.291569 7.181805 5.953488 6.247742 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 251 IGF1R 6.349437 7.736671 7.159566 7.386858 NA Retinopathy NA NA NA

252 IGF2 7.707059 11.51954 9.082868 9.613996 NA Retinopathy NA Nephropathy Neuropathy

253 IGFBP1 2.783373 6.495862 4.404192 4.894954 NA NA NA Nephropathy NA

254 IGFBP3 7.990738 10.12479 8.827023 9.163363 NA NA NA Nephropathy NA

255 IGFBP5 5.437674 8.574477 6.459542 6.999185 NA NA NA NA Neuropathy

121

256 IGFBP7 4.204401 5.554504 4.669695 4.890867 NA NA NA Nephropathy NA

257 IL10 4.262062 5.583049 4.762914 4.993274 NA NA NA Nephropathy Neuropathy

258 IL17A 3.143078 4.160134 3.553325 3.744071 NA Retinopathy NA Nephropathy NA

259 IL18 4.158367 5.174885 4.486403 4.674302 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 260 IL1B 6.149892 8.024578 6.728927 6.996043 Cardiovascular Retinopathy NA Nephropathy NA diseases 261 IL1RN 5.394891 6.3575 5.674422 5.835878 NA NA NA Nephropathy NA

262 IL4 3.650941 4.699379 3.950667 4.154142 NA NA NA NA Neuropathy

263 IL6 4.609095 8.206552 6.100823 6.601205 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 264 ILK 8.71753 9.662525 9.154467 9.293147 NA NA NA Nephropathy NA

265 INS 5.529962 6.574497 6.005401 6.181647 Cardiovascular Retinopathy Atherosclerosi NA NA diseases s 266 IRAK1 6.104591 7.30224 6.566319 6.77601 NA NA NA NA Neuropathy

267 IRS1 7.762456 9.278636 8.339591 8.650858 NA Retinopathy NA NA NA

268 IRS2 6.333218 8.223839 7.225663 7.528572 NA NA Atherosclerosi Nephropathy Neuropathy s 269 ITGA2 4.853327 6.150718 5.377349 5.624778 NA Retinopathy NA NA NA

270 ITGAM 5.182426 6.231647 5.517941 5.728768 NA Retinopathy NA Nephropathy NA

271 ITGB3 5.4771 8.009275 6.211691 6.628545 NA Retinopathy NA NA NA

272 JAK2 4.165902 5.619428 4.925352 5.171126 NA NA NA Nephropathy NA

273 KCNQ1 4.194451 6.93833 5.154566 5.584782 NA NA NA Nephropathy NA

274 KDM1A 7.692163 8.422363 7.954063 8.073919 NA Retinopathy NA NA NA

275 KL 3.165877 4.604896 3.853362 4.073203 NA NA NA Nephropathy NA

276 KLF10 7.988101 11.05382 9.226843 9.622897 NA NA NA Nephropathy NA

277 KLF6 7.708695 8.769184 8.164972 8.361583 NA NA NA Nephropathy NA

278 L1CAM 4.810125 7.405396 6.012741 6.441894 NA Retinopathy NA NA NA

279 LAMC1 7.600481 9.260018 8.456951 8.702166 NA NA NA Nephropathy NA

280 LDLR 5.658336 7.101962 6.327961 6.558104 Cardiovascular NA Atherosclerosi NA NA diseases s 281 LEP 4.979487 6.957344 5.42884 5.734946 NA NA Atherosclerosi NA Neuropathy s 282 LIMK2 4.977079 6.810019 5.734862 6.080702 NA NA NA Nephropathy NA

283 LMNA 7.383858 8.763648 7.9582 8.202386 NA NA NA Nephropathy NA

284 LPA 2.890763 3.766391 3.356708 3.496878 Cardiovascular NA Atherosclerosi NA NA diseases s 285 LPL 6.193283 8.312666 6.754903 7.091525 Cardiovascular NA Atherosclerosi Nephropathy Neuropathy diseases s 286 LPO 6.26688 7.110802 6.563145 6.721247 NA Retinopathy NA NA NA

287 LRP2 3.120488 4.130683 3.540145 3.706535 NA NA NA Nephropathy NA

288 LTA 6.331451 7.141227 6.692038 6.833348 NA NA NA Nephropathy NA

289 MALT1 5.19368 6.510883 5.792161 6.022592 NA NA NA Nephropathy NA

290 MAP3K5 5.555726 7.268457 6.261366 6.537369 Cardiovascular NA NA Nephropathy NA diseases 291 MAPK1 4.802512 6.009998 5.377981 5.58945 NA NA NA Nephropathy Neuropathy

292 MAPK14 7.600288 8.639849 7.963144 8.148918 NA NA NA Nephropathy NA

293 MAPK7 6.887805 7.946151 7.215858 7.420448 NA Retinopathy NA NA NA

294 MBL2 2.646018 4.154338 3.325179 3.543041 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 295 MBP 5.58799 7.18707 6.351879 6.635901 NA NA NA NA Neuropathy

296 MCAM 5.906687 6.903928 6.437393 6.596833 NA NA NA Nephropathy NA

297 MEP1B 5.321741 6.074168 5.566972 5.710455 NA NA NA Nephropathy NA

298 MIF 8.797283 9.855447 9.222503 9.41338 NA NA Atherosclerosi Nephropathy Neuropathy s 299 MME 6.336266 9.196846 7.440505 7.896677 NA NA NA NA Neuropathy

122

300 MMP14 6.643591 8.051962 7.224046 7.439325 NA NA NA Nephropathy NA

301 MMP16 3.677986 4.917297 4.063337 4.254693 NA NA NA Nephropathy NA

302 MMP2 5.150439 6.599081 5.535325 5.819295 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 303 MMP24 5.129914 6.242207 5.529386 5.768206 NA NA NA Nephropathy NA

304 MMP9 5.969224 6.97941 6.348105 6.523359 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 305 MOK 5.779702 7.222445 6.202725 6.454093 NA NA Atherosclerosi Nephropathy NA s 306 MPO 5.016933 5.911691 5.364717 5.526862 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 307 MRPL28 7.229526 8.332368 7.876919 8.061284 NA Retinopathy NA NA NA

308 MSH2 5.840132 7.155896 6.36081 6.607153 Cardiovascular NA NA NA NA diseases 309 MTHFR 6.797196 7.595029 7.123309 7.27044 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 310 MTOR 5.612271 7.129884 6.480694 6.711304 NA NA NA Nephropathy NA

311 MYD88 6.910455 8.90597 7.81467 8.174635 NA NA NA Nephropathy NA

312 MYH9 7.749187 10.2211 9.004157 9.442883 NA NA NA Nephropathy NA

313 NAGLU 6.310695 7.648966 6.919688 7.148051 Cardiovascular Retinopathy NA NA NA diseases 314 NAMPT 5.354305 8.102 6.202707 6.633516 Cardiovascular NA NA NA NA diseases 315 NCALD 3.790136 5.404821 4.310463 4.558509 NA NA NA Nephropathy NA

316 NCF2 4.902227 6.075015 5.255545 5.44797 NA NA NA Nephropathy NA

317 NDUFS3 9.636872 10.51535 9.951247 10.12225 NA NA NA Nephropathy NA

318 NEDD4L 5.512158 7.186824 6.217946 6.535468 NA NA NA Nephropathy NA

319 NFE2 4.527656 6.060312 5.084573 5.345757 NA NA NA Nephropathy NA

320 NFE2L2 5.980106 7.030878 6.400785 6.562074 NA Retinopathy NA Nephropathy Neuropathy

321 NFKBIA 7.918795 10.13364 8.540767 8.975828 NA NA NA Nephropathy NA

322 NGF 6.462222 7.944712 6.960387 7.224907 NA NA NA Nephropathy Neuropathy

323 NGFR 5.94767 7.734465 6.671526 7.028155 NA NA NA NA Neuropathy

324 NLRP3 4.43244 5.646168 4.842284 5.016662 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 325 NME2 9.95094 11.2975 10.4879 10.72875 NA Retinopathy NA NA NA

326 NOS1 4.478571 6.240946 5.253054 5.506715 NA Retinopathy NA Nephropathy Neuropathy

327 NOS2 5.934471 6.816603 6.243975 6.397855 NA Retinopathy NA Nephropathy NA

328 NOS3 5.00751 6.453014 5.544085 5.854609 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 329 NOV 5.677885 7.0758 6.176625 6.417762 NA NA NA Nephropathy NA

330 NOX1 2.633156 3.491897 2.989565 3.113006 NA NA NA Nephropathy NA

331 NPHS1 4.138194 5.889309 5.015943 5.334714 NA NA NA Nephropathy NA

332 NPPA 7.554719 8.433486 7.946806 8.097466 Cardiovascular NA NA NA NA diseases 333 NPY 5.120335 6.106811 5.577909 5.733629 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 334 NPY2R 5.218208 6.233934 5.650484 5.849882 Cardiovascular NA NA NA NA diseases 335 NPY5R 4.206422 5.858874 5.010399 5.294689 Cardiovascular NA NA NA NA diseases 336 NQO1 6.705341 8.827954 7.713794 8.07107 Cardiovascular NA Atherosclerosi NA NA diseases s 337 NR1H3 4.736396 6.198648 5.34927 5.561817 NA NA NA Nephropathy NA

338 NR3C2 6.349946 8.184286 7.293086 7.567449 Cardiovascular NA NA NA NA diseases 339 NRF1 6.314479 7.163793 6.611669 6.763305 NA NA NA NA Neuropathy

340 NSA2 9.219872 10.59414 9.680041 9.896998 NA NA NA Nephropathy NA

341 NTF3 6.887463 8.246781 7.399377 7.658161 NA NA NA NA Neuropathy

342 NTS 4.355219 5.880039 4.87518 5.138936 Cardiovascular NA NA NA NA diseases 343 NUCB2 6.949606 8.325142 7.494375 7.765949 Cardiovascular Retinopathy NA NA NA diseases

123

344 ONECUT 4.963402 6.33098 5.493073 5.754558 NA NA NA Nephropathy NA 1 345 OSM 5.617456 6.900505 5.966042 6.146349 NA NA NA Nephropathy NA

346 OXT 5.748333 7.132526 6.221371 6.481332 Cardiovascular NA NA NA NA diseases 347 P2RX3 4.722383 6.346428 5.30772 5.609702 NA NA NA NA Neuropathy

348 P2RY1 3.9998 5.070084 4.51376 4.707754 NA NA NA NA Neuropathy

349 P2RY2 6.283852 7.512437 6.647918 6.846265 NA NA NA NA Neuropathy

350 PARP1 7.929397 9.017041 8.604901 8.784788 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 351 PC 5.44571 6.931326 6.158402 6.37451 NA NA NA Nephropathy NA

352 PDE5A 5.570028 6.609087 5.9901 6.167647 NA NA NA Nephropathy Neuropathy

353 PDGFA 5.926989 7.831959 6.786649 7.125047 NA NA NA Nephropathy NA

354 PDGFB 6.265907 7.242588 6.741609 6.895645 NA NA NA Nephropathy NA

355 PDGFRB 7.516798 9.723296 8.544151 8.887054 NA NA NA Nephropathy NA

356 PDHX 8.601837 9.759265 9.152187 9.349837 NA Retinopathy NA NA NA

357 PDK1 5.963844 7.242177 6.380385 6.607508 NA NA NA Nephropathy NA

358 PDPK1 6.729677 7.972294 7.339868 7.558631 NA NA NA Nephropathy NA

359 PEBP1 9.429303 10.62641 10.02829 10.17992 NA NA NA Nephropathy NA

360 PECAM1 4.09671 5.304429 4.733621 4.948378 NA NA NA NA Neuropathy

361 PFKFB2 5.951426 7.039357 6.582423 6.742777 NA NA NA Nephropathy NA

362 PGF 6.217808 8.067182 6.78762 7.116046 Cardiovascular NA NA NA NA diseases 363 PHACTR 3.887325 4.771472 4.203078 4.363184 Cardiovascular NA NA NA NA 1 diseases 364 PICK1 6.565418 7.888012 7.13239 7.385467 NA NA NA Nephropathy NA

365 PIGF 7.890334 8.824667 8.177463 8.34829 NA Retinopathy NA NA NA

366 PIK3CA 6.140147 7.223033 6.669918 6.869261 NA NA NA Nephropathy NA

367 PIP 6.00252 6.58677 6.247013 6.34348 NA NA NA Nephropathy NA

368 PLA2G2 5.835889 9.165887 6.44402 6.912397 NA NA Atherosclerosi NA NA A s 369 PLIN1 6.023621 7.785095 6.727112 7.001832 Cardiovascular NA NA NA NA diseases 370 PLIN2 7.936797 10.54495 8.958214 9.460567 Cardiovascular NA NA NA NA diseases 371 PLN 8.20557 9.246512 8.594362 8.79254 Cardiovascular NA NA NA NA diseases 372 PLTP 5.045564 7.239462 6.09982 6.479257 NA NA Atherosclerosi NA NA s 373 PLXDC1 5.030103 6.558049 5.736402 5.988865 NA Retinopathy NA NA NA

374 PMP22 5.255569 6.902638 6.079908 6.358377 NA NA NA NA Neuropathy

375 POLR2D 5.211879 6.878609 5.990957 6.267284 NA Retinopathy NA NA NA

376 POMC 5.908469 7.03861 6.256757 6.46325 Cardiovascular NA NA NA Neuropathy diseases 377 PON1 3.931391 5.604373 4.406045 4.666868 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy diseases s 378 PON2 7.111086 8.598349 7.612672 7.829569 NA NA Atherosclerosi Nephropathy NA s 379 PON3 5.892132 6.536832 6.1485 6.260095 Cardiovascular NA Atherosclerosi NA NA diseases s 380 POSTN 4.852852 7.170126 6.202002 6.582958 NA Retinopathy NA Nephropathy NA

381 PPARA 5.224408 6.404521 5.630814 5.850278 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 382 PPARG 4.684888 5.936697 5.195771 5.430868 NA Retinopathy Atherosclerosi Nephropathy NA s 383 PPIA 10.7487 11.75115 10.96948 11.11234 Cardiovascular NA NA Nephropathy NA diseases 384 PPY 3.942451 5.703513 4.7809 5.082351 NA NA NA NA Neuropathy

385 PRCP 4.705649 7.233247 5.884628 6.313517 Cardiovascular NA Atherosclerosi Nephropathy NA diseases s 386 PRDX1 10.60233 11.59738 10.95544 11.13813 Cardiovascular NA NA NA NA diseases 387 PRDX2 5.941859 7.782227 6.746727 7.137548 Cardiovascular NA NA NA NA diseases

124

388 PRDX4 8.227131 9.707048 9.015985 9.261308 Cardiovascular NA NA NA NA diseases 389 PRDX6 10.28513 11.45307 10.75934 10.97103 Cardiovascular NA NA NA NA diseases 390 PRKAA1 2.940003 4.025008 3.274861 3.424915 NA NA NA Nephropathy NA

391 PRKCB 3.595595 4.834404 4.193121 4.384477 NA NA NA Nephropathy Neuropathy

392 PRKCE 6.326369 7.469376 6.729108 6.934136 NA NA NA Nephropathy NA

393 PRKG1 4.955623 7.363008 5.75503 6.153321 NA NA NA NA Neuropathy

394 PRMT2 5.93033 7.16283 6.409642 6.605528 NA NA Atherosclerosi NA NA s 395 PROC 5.553265 6.546316 5.982584 6.155468 NA NA NA Nephropathy NA

396 PROM1 3.280058 4.396901 3.866446 4.066465 NA NA NA NA Neuropathy

397 PSIP1 3.256416 4.559297 3.909248 4.153805 NA Retinopathy NA NA NA

398 PSMA6 10.38494 11.27572 10.76104 10.92135 Cardiovascular NA NA Nephropathy NA diseases 399 PSMD9 7.751612 8.783309 8.069422 8.22771 NA Retinopathy NA Nephropathy Neuropathy

400 PTEN 6.381941 7.757269 6.957568 7.225877 NA NA NA Nephropathy Neuropathy

401 PTGDS 7.933429 10.25638 8.660472 9.070924 NA NA Atherosclerosi Nephropathy NA s 402 PTGER1 6.521011 7.871865 7.000341 7.19317 NA NA NA Nephropathy NA

403 PTGER4 5.327821 6.393638 5.7784 5.984611 NA NA NA Nephropathy NA

404 PTGES 6.835172 8.247302 7.350319 7.599903 NA NA NA Nephropathy NA

405 PTGS2 4.179011 5.810947 4.71436 4.92399 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 406 PTH 3.041456 3.803192 3.247249 3.384438 Cardiovascular NA NA Nephropathy NA diseases 407 PTH1R 6.905503 7.921917 7.130736 7.324952 NA NA NA Nephropathy NA

408 PTPN1 6.501547 7.835661 7.107561 7.300395 Cardiovascular NA NA Nephropathy NA diseases 409 PTX3 5.844531 7.840049 6.631301 6.977316 NA Retinopathy Atherosclerosi Nephropathy NA s 410 PVT1 5.655119 6.658598 6.061572 6.261206 NA NA NA Nephropathy NA

411 RAF1 6.353674 7.699464 7.107692 7.341864 NA Retinopathy NA Nephropathy NA

412 RARRES2 7.073597 10.25864 8.495429 8.932165 Cardiovascular NA NA NA NA diseases 413 RBP1 6.167175 8.984003 6.875497 7.335175 NA Retinopathy NA NA NA

414 RBP4 4.795792 6.973236 5.317476 5.689075 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 415 RCAN1 6.487706 8.353736 7.313084 7.609672 NA NA NA Nephropathy NA

416 REG1A 5.321132 6.311841 5.631706 5.75595 NA NA NA Nephropathy NA

417 RELA 6.784276 8.310685 7.468979 7.716327 NA Retinopathy NA Nephropathy NA

418 REN 5.195739 5.989041 5.502637 5.643165 Cardiovascular NA Atherosclerosi NA NA diseases s 419 RGN 5.852612 6.74974 6.20951 6.401584 NA NA NA Nephropathy NA

420 RHO 5.466376 6.660315 5.778986 5.958765 NA Retinopathy NA NA NA

421 RHOA 9.242308 10.62027 9.748214 9.974913 NA NA NA NA Neuropathy

422 RHOD 6.602057 7.542411 6.987305 7.171478 NA NA NA Nephropathy NA

423 ROCK1 3.436263 4.556044 3.829843 4.010693 NA NA NA Nephropathy NA

424 ROCK2 7.270584 8.746966 8.130017 8.352988 NA NA Atherosclerosi NA NA s 425 RPS12 12.0616 12.85675 12.38806 12.49821 NA NA NA Nephropathy NA

426 RPS6 11.80437 12.64956 12.11806 12.26444 NA NA NA Nephropathy NA

427 RREB1 6.987334 8.060415 7.472176 7.671129 NA NA NA Nephropathy NA

428 RTN1 3.965185 5.450277 4.470701 4.703469 NA NA NA Nephropathy NA

429 S100A12 5.415464 6.645335 5.894625 6.092053 Cardiovascular Retinopathy NA NA NA diseases 430 SARDH 4.087247 5.639602 4.66139 4.877771 NA Retinopathy NA NA NA

431 SCARB1 6.781549 7.55513 7.104999 7.257136 NA NA Atherosclerosi NA NA s

125

432 SELE 3.453886 4.463574 3.786859 3.980476 NA NA NA Nephropathy NA

433 SEMA3A 5.07184 6.706327 5.579654 5.799778 NA NA NA Nephropathy NA

434 SERPINB 6.912181 8.398401 7.373293 7.641462 NA NA NA Nephropathy NA 7 435 SERPINE 6.310747 8.537486 7.257474 7.607388 NA NA NA Nephropathy NA 1 436 SERPINF 10.38034 12.0963 10.86364 11.18528 NA Retinopathy NA Nephropathy Neuropathy 1 437 SERPINF 5.501606 7.470708 6.379207 6.742141 NA NA NA Nephropathy NA 2 438 SFI1 6.435428 7.211752 6.719965 6.857967 NA NA NA Nephropathy NA

439 SGK1 7.652848 9.54666 8.539524 8.890921 NA NA NA Nephropathy NA

440 SHBG 6.091135 7.189462 6.527474 6.705811 Cardiovascular NA NA NA NA diseases 441 SLC12A3 5.524172 6.545174 5.974189 6.150118 NA NA NA Nephropathy NA

442 SLC22A6 5.780843 6.878306 6.192659 6.41059 NA NA NA Nephropathy NA

443 SLC2A1 6.126186 7.236641 6.42064 6.610362 Cardiovascular NA NA Nephropathy NA diseases 444 SLC2A2 2.953095 4.636528 3.386288 3.596921 NA NA NA Nephropathy NA

445 SLC2A3 6.757253 8.635013 7.467379 7.714157 NA NA NA NA Neuropathy

446 SLC2A4 6.314095 7.167686 6.717483 6.873804 Cardiovascular NA NA Nephropathy Neuropathy diseases 447 SLC5A2 7.262889 8.123932 7.651739 7.797193 Cardiovascular NA NA NA NA diseases 448 SLC9A1 3.77832 4.968578 4.219396 4.433418 NA NA NA Nephropathy NA

449 SMAD1 5.027331 6.390992 5.70849 5.926965 NA NA NA Nephropathy NA

450 SMAD7 5.438334 8.08587 6.40017 6.805124 NA NA NA Nephropathy NA

451 SMG1 3.161501 6.489245 4.802516 5.393207 NA Retinopathy NA NA NA

452 SMPD1 6.797298 8.654654 7.873505 8.139569 NA Retinopathy NA NA NA

453 SOCS1 5.769852 6.707946 6.092093 6.265565 NA NA NA Nephropathy NA

454 SOCS2 3.869847 6.441182 4.820203 5.289659 NA NA NA Nephropathy NA

455 SOCS3 5.33855 7.483662 6.172499 6.627612 NA Retinopathy NA Nephropathy NA

456 SOD1 10.61913 11.37252 10.89741 11.02799 NA Retinopathy NA Nephropathy NA

457 SOD2 7.84098 10.32402 8.875806 9.310595 NA Retinopathy NA NA Neuropathy

458 SORBS2 3.138763 4.672616 3.743991 4.026419 NA NA NA Nephropathy NA

459 SOX9 4.930988 6.93113 5.732457 6.084943 NA NA NA Nephropathy NA

460 SPARC 10.63066 11.81475 11.06649 11.31781 NA Retinopathy NA Nephropathy NA

461 SPP1 3.074856 6.0271 3.770553 4.165416 Cardiovascular Retinopathy NA Nephropathy NA diseases 462 SRC 4.546852 6.372233 5.154929 5.455964 NA NA NA Nephropathy NA

463 SREBF1 5.114053 6.885508 5.659409 5.938987 NA NA NA Nephropathy Neuropathy

464 SRGN 3.480772 5.196084 4.275873 4.57462 NA Retinopathy NA NA NA

465 SST 3.738774 5.688565 4.495557 4.856062 NA Retinopathy NA Nephropathy NA

466 STAT1 7.995836 9.567402 8.570314 8.869704 NA NA NA Nephropathy NA

467 STAT3 7.478864 9.469814 8.425897 8.744674 NA Retinopathy NA Nephropathy NA

468 STAT5A 6.423193 7.487767 6.773697 6.957462 NA NA NA Nephropathy NA

469 STK11 7.089448 7.986494 7.4257 7.584527 NA NA NA Nephropathy NA

470 SUMO4 8.586307 9.68631 9.000143 9.168746 Cardiovascular NA NA Nephropathy NA diseases 471 TACR1 4.153679 5.392831 4.585317 4.780743 Cardiovascular NA NA NA NA diseases 472 TCF7L2 6.130446 7.406197 6.815648 7.031293 Cardiovascular Retinopathy Atherosclerosi Nephropathy NA diseases s 473 TF 3.797562 5.170834 4.322352 4.571199 NA NA NA Nephropathy NA

474 TFAM 5.89039 7.167185 6.387656 6.604485 NA NA NA NA Neuropathy

475 TGFB1 5.840164 6.700912 6.19035 6.353028 Cardiovascular NA NA Nephropathy NA diseases

126

476 TGFBR1 4.706744 6.558848 5.385577 5.736909 NA NA NA Nephropathy NA

477 TH 4.057301 5.606556 4.634147 4.865043 NA Retinopathy NA NA Neuropathy

478 THBD 6.140522 8.913499 7.42671 7.809429 NA NA NA Nephropathy NA

479 THBS1 5.718347 8.164884 6.560299 7.000628 NA Retinopathy NA Nephropathy NA

480 THBS2 7.125112 8.945527 8.076095 8.354044 NA NA NA Nephropathy NA

481 TIMM44 7.348659 8.190239 7.729321 7.897833 NA NA NA Nephropathy NA

482 TIMP1 9.422222 10.5413 9.867688 10.09068 NA Retinopathy NA NA NA

483 TIMP2 6.52718 7.677258 6.996979 7.180835 NA NA NA Nephropathy NA

484 TIMP3 7.269597 9.664776 8.141402 8.528593 NA Retinopathy Atherosclerosi Nephropathy NA s 485 TKT 6.829759 8.385884 7.442887 7.735957 NA NA NA Nephropathy Neuropathy

486 TLR2 5.410615 6.661197 5.848994 6.03086 NA NA NA Nephropathy NA

487 TNF 5.432874 6.777031 5.80839 6.006284 NA Retinopathy NA Nephropathy Neuropathy

488 TNFAIP8 6.009931 7.759757 6.527697 6.804099 NA NA NA Nephropathy NA

489 TNFRSF1 2.702139 5.1382 3.449128 3.901126 Cardiovascular Retinopathy Atherosclerosi Nephropathy Neuropathy 1B diseases s 490 TNFRSF1 5.118189 7.469033 5.778064 6.144237 NA NA NA NA Neuropathy B 491 TPM1 4.992963 6.799614 5.798494 6.112724 Cardiovascular NA NA NA NA diseases 492 TRAF6 6.589673 7.886655 7.068855 7.294768 NA NA NA NA Neuropathy

493 TRH 6.346424 8.163345 6.891084 7.158786 NA NA NA NA Neuropathy

494 TRPA1 4.97642 5.684364 5.21212 5.33157 NA NA NA NA Neuropathy

495 TRPC1 5.444825 6.508009 5.900695 6.110943 NA NA NA Nephropathy NA

496 TRPC6 2.806865 3.642876 3.123966 3.263589 NA NA Atherosclerosi Nephropathy NA s 497 TSC1 7.070113 8.01325 7.660794 7.802235 NA NA NA Nephropathy NA

498 TSC2 5.302389 7.06091 6.193363 6.452431 NA NA NA Nephropathy NA

499 TSC22D1 8.746304 10.60136 9.608469 9.867704 NA NA NA Nephropathy NA

500 TSPO 8.294059 9.737866 8.969808 9.193698 NA NA NA NA Neuropathy

501 TUBB3 7.732717 9.803497 8.647783 8.998755 NA Retinopathy NA NA NA

502 TXN 8.843111 10.79296 9.582859 9.842113 Cardiovascular NA Atherosclerosi NA NA diseases s 503 TXNIP 8.925473 11.79754 10.5264 11.05542 NA Retinopathy Atherosclerosi Nephropathy NA s 504 UCP2 7.317656 9.495488 8.110037 8.470304 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 505 UMOD 5.740019 6.590704 6.073938 6.224556 NA NA NA Nephropathy NA

506 UNC13A 5.442072 6.52135 5.860053 6.059333 NA NA NA NA Neuropathy

507 UNC13B 7.113373 8.478418 7.879357 8.110892 NA NA NA Nephropathy NA

508 UNC5B 6.849404 8.527205 7.482298 7.742264 NA NA NA Nephropathy NA

509 USF2 8.163005 8.935314 8.392521 8.52645 NA NA NA Nephropathy NA

510 UTRN 5.816897 7.103047 6.370948 6.600218 NA NA NA Nephropathy NA

511 VCAM1 4.41284 7.045442 5.584469 6.013522 Cardiovascular NA Atherosclerosi NA NA diseases s 512 VDAC1 9.6474 10.6809 10.22664 10.38149 NA NA NA Nephropathy NA

513 VDAC2 10.33931 11.21194 10.76587 10.90623 NA NA NA Nephropathy NA

514 VDR 6.270435 8.032485 6.839203 7.142935 Cardiovascular Retinopathy NA Nephropathy NA diseases 515 VEGFA 9.272048 10.6418 9.793724 10.06658 NA Retinopathy Atherosclerosi Nephropathy Neuropathy s 516 VEGFC 6.059132 8.304327 7.230985 7.641603 NA Retinopathy NA NA NA

517 VIP 2.830958 3.4644 3.072176 3.183666 NA NA NA NA Neuropathy

518 VWF 7.39045 8.349322 7.833223 7.977765 Cardiovascular NA NA Nephropathy Neuropathy diseases 519 WFS1 5.980935 7.049557 6.456246 6.618522 NA NA NA Nephropathy NA

127

520 WT1 3.166461 5.612518 4.321201 4.781425 NA NA NA Nephropathy NA

521 XBP1 7.787794 8.862635 8.231507 8.430183 NA NA NA Nephropathy NA

522 XIAP 4.586822 5.698018 4.979393 5.152864 NA NA NA NA Neuropathy

523 XRCC1 6.95705 8.057738 7.325924 7.555797 Cardiovascular Retinopathy NA NA NA diseases 524 ZEB2 4.972371 7.29594 5.908365 6.383669 NA NA NA Nephropathy NA

Table A.6: table for pancreatic tissue

Genes Actual Actual 99% CI 99% CI complication1 complication2 complication3 complication4 complication5 Min Max Min Max 1 ABCA1 5.523461 8.063753 6.543235 6.847324 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 2 ABCG1 5.422873 8.073397 6.580141 6.921017 Cardiovascular NA Atherosclerosis NA NA diseases 3 ABO 5.483735 6.627879 5.928385 6.093309 Cardiovascular NA NA NA NA diseases 4 ACACB 5.712529 7.00137 6.190652 6.366425 NA NA NA Nephropathy NA

5 ACAT1 8.093719 9.625589 8.823604 9.050079 NA NA Atherosclerosis NA NA

6 ACE 5.357409 6.352226 5.769112 5.894575 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 7 ACE2 4.306985 7.052349 5.302766 5.67563 Cardiovascular NA NA Nephropathy NA diseases 8 ACSL1 7.474079 9.887825 8.761283 9.094519 NA NA Atherosclerosis NA NA

9 ACVRL1 5.750806 7.047577 6.390668 6.582405 NA NA NA Nephropathy NA

10 ADAM10 8.892279 10.54212 9.830488 10.08146 NA NA NA Nephropathy NA

11 ADAM17 7.25505 8.236442 7.750701 7.893609 NA NA Atherosclerosis Nephropathy NA

12 ADAMTS 5.227313 6.091172 5.540364 5.661451 NA NA NA Nephropathy NA 13 13 ADCYAP 7.207002 10.59901 8.515928 9.045171 NA Retinopathy NA Nephropathy NA 1 14 ADH1B 3.603943 4.791921 4.043197 4.237308 NA NA NA Nephropathy Neuropathy

15 ADIPOQ 4.046141 4.930794 4.332163 4.451851 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 16 ADIPOR 8.695019 9.640131 9.122843 9.240441 Cardiovascular NA NA NA NA 1 diseases 17 ADK 7.570498 8.907913 8.126609 8.355139 NA Retinopathy NA NA NA

18 ADM 7.29715 9.532788 8.050945 8.3749 NA Retinopathy NA Nephropathy Neuropathy

19 ADRA2B 5.736515 6.852794 6.222238 6.369931 NA NA NA NA Neuropathy

20 AGT 6.578762 8.838321 7.62609 8.025363 NA NA NA Nephropathy Neuropathy

21 AGTR1 5.307421 6.227575 5.667349 5.822858 NA NA NA Nephropathy NA

22 AHSA1 8.035345 9.461254 8.798391 8.976168 Cardiovascular Retinopathy NA Nephropathy NA diseases 23 AHSG 3.300951 4.00798 3.557831 3.663086 Cardiovascular Retinopathy NA Nephropathy NA diseases 24 AKR1B1 8.016819 9.499066 8.694187 8.934745 NA Retinopathy NA Nephropathy Neuropathy

25 AKR1B10 6.560765 10.91746 8.810794 9.465571 NA NA NA Nephropathy NA

26 AKT1 8.171356 8.982617 8.54732 8.67335 Cardiovascular Retinopathy NA Nephropathy NA diseases 27 ALB 6.012289 12.55381 8.608979 9.61932 NA NA Atherosclerosis Nephropathy Neuropathy

28 ALDH1A 9.890338 12.58073 11.29356 11.73381 NA NA NA Nephropathy NA 1 29 ALDH2 7.646108 9.340503 8.506118 8.775605 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 30 ALOX5A 5.228461 7.188117 5.980324 6.234757 NA NA Atherosclerosis Nephropathy NA P 31 ALPK1 4.858195 6.866946 5.873803 6.142654 Cardiovascular NA NA NA NA diseases 32 ALPL 4.499533 5.522812 4.92442 5.065517 NA NA NA Nephropathy NA

33 AMBP 6.870136 10.43525 8.038805 8.535526 NA NA NA Nephropathy NA

34 ANG 5.541088 7.793875 6.740629 7.047199 NA NA NA Nephropathy NA

128

35 ANGPT2 4.986323 7.936001 6.660617 7.091538 NA Retinopathy NA NA NA

36 ANGPTL 5.773716 7.32612 6.580341 6.805352 NA NA Atherosclerosis Nephropathy NA 2 37 ANGPTL 5.839993 8.346067 6.78514 7.127152 NA Retinopathy NA Nephropathy NA 4 38 AOC2 3.926474 4.989211 4.424611 4.570491 NA NA NA Nephropathy NA

39 AOC3 4.328235 5.362542 4.734709 4.896647 NA Retinopathy NA NA NA

40 APC 5.787359 7.828854 6.642916 6.928294 NA NA NA Nephropathy NA

41 API5 8.728805 9.438335 9.014151 9.119691 NA Retinopathy NA NA NA

42 APLNR 4.681263 6.227324 5.237953 5.473473 NA NA NA Nephropathy NA

43 APOA1 5.638533 6.483764 5.98848 6.126712 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 44 APOB 3.44475 4.621697 4.092925 4.250947 Cardiovascular Retinopathy NA NA Neuropathy diseases 45 APOC1 4.389718 6.008841 5.220294 5.443301 NA NA NA Nephropathy NA

46 APOC3 4.679611 5.473277 4.994614 5.123293 Cardiovascular NA NA Nephropathy NA diseases 47 APOE 6.397196 7.176467 6.719798 6.85657 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 48 APOH 5.244803 8.783618 7.174124 7.703703 Cardiovascular NA NA NA NA diseases 49 APOL1 6.212055 8.802904 7.102114 7.492167 Cardiovascular NA NA Nephropathy NA diseases 50 APPL1 8.273143 9.33453 8.648634 8.765165 NA NA Atherosclerosis Nephropathy NA

51 AQP1 5.201012 9.658003 7.01033 7.664833 NA Retinopathy NA NA NA

52 AQP4 3.927671 5.911273 4.684476 4.937883 NA Retinopathy NA NA NA

53 AQP5 4.885652 5.877931 5.306629 5.446193 NA NA NA Nephropathy NA

54 AR 4.592616 5.660518 5.008511 5.169402 NA NA NA Nephropathy NA

55 ASPA 2.283658 3.227749 2.575313 2.723559 NA NA NA NA Neuropathy

56 ATF4 7.486921 9.504348 8.177945 8.42953 NA Retinopathy NA Nephropathy NA

57 ATM 6.434657 7.819168 7.090296 7.269411 Cardiovascular NA NA NA NA diseases 58 ATP2A2 8.601505 10.14537 9.402476 9.618832 NA NA NA NA Neuropathy

59 B2M 11.10657 12.79716 11.85948 12.11264 NA NA Atherosclerosis Nephropathy NA

60 BAAT 4.114361 6.755136 5.033952 5.467875 NA NA Atherosclerosis NA NA

61 BAMBI 7.375217 8.736263 7.914647 8.146386 NA NA NA Nephropathy NA

62 BASP1 6.579451 8.158066 7.267789 7.481705 NA NA NA Nephropathy NA

63 BCL2 5.551903 6.281942 5.78606 5.895255 NA NA NA Nephropathy NA

64 BDKRB1 5.147263 8.562686 6.188832 6.554193 NA NA NA NA Neuropathy

65 BDKRB2 6.24929 7.640416 6.776542 6.976134 NA NA NA NA Neuropathy

66 BDNF 2.845789 3.804469 3.35111 3.474643 NA Retinopathy NA NA Neuropathy

67 BMP2 6.552558 8.291469 7.247506 7.504881 NA NA Atherosclerosis NA NA

68 BMP4 4.749033 6.211463 5.397857 5.601275 NA NA NA Nephropathy NA

69 BNIP3 8.219237 9.305214 8.595685 8.743522 Cardiovascular NA NA NA NA diseases 70 C5 3.967286 7.375402 5.075516 5.580132 NA Retinopathy NA Nephropathy NA

71 CACNA1 6.488803 7.498244 6.810596 6.968925 NA NA NA NA Neuropathy H 72 CAPN10 5.747983 6.480826 6.016864 6.130399 NA NA Atherosclerosis NA NA

73 CAT 7.121868 8.938272 8.008262 8.297621 NA Retinopathy NA Nephropathy NA

74 CAV1 5.602585 7.500513 6.545098 6.82655 NA NA NA Nephropathy Neuropathy

75 CCK 4.861491 5.653985 5.172911 5.304181 NA NA NA Nephropathy Neuropathy

76 CCKAR 4.977193 6.282539 5.320965 5.507376 NA NA NA Nephropathy NA

77 CCL2 8.307276 11.83558 9.852191 10.4157 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

78 CCL20 4.864328 10.14459 6.534742 7.368109 NA NA NA Nephropathy NA

129

79 CCL5 4.577923 5.6916 4.96737 5.132534 NA NA NA Nephropathy NA

80 CCR1 4.032878 5.311348 4.618967 4.779044 NA NA NA Nephropathy NA

81 CCR2 3.191082 3.865843 3.473824 3.581402 NA NA Atherosclerosis Nephropathy NA

82 CD160 3.067363 3.940112 3.401968 3.536111 NA Retinopathy NA NA NA

83 CD163 4.499382 6.066501 5.086874 5.328158 NA Retinopathy Atherosclerosis NA Neuropathy

84 CD247 4.401506 5.529449 4.847684 4.999035 Cardiovascular NA NA NA NA diseases 85 CD2AP 8.015354 10.04025 9.087039 9.376137 NA NA NA Nephropathy NA

86 CD34 4.746151 6.230674 5.318831 5.55074 NA NA NA NA Neuropathy

87 CD36 5.738136 8.350353 6.704553 7.059206 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 88 CD38 4.065694 5.012109 4.457492 4.602899 NA NA NA Nephropathy NA

89 CD4 5.200877 6.615114 5.833721 6.029132 Cardiovascular NA Atherosclerosis NA NA diseases 90 CD40 5.976847 7.055753 6.384055 6.528581 Cardiovascular NA Atherosclerosis NA NA diseases 91 CD40LG 2.584777 3.46261 2.897264 3.038199 Cardiovascular NA NA Nephropathy NA diseases 92 CD47 8.971429 11.07904 9.923118 10.1985 NA NA NA Nephropathy NA

93 CD59 10.39426 12.10275 11.11973 11.34282 NA Retinopathy NA NA NA

94 CD63 11.00901 12.03518 11.41997 11.5568 NA NA NA Nephropathy NA

95 CD68 8.358022 9.772518 8.987562 9.189526 NA NA NA Nephropathy NA

96 CD69 3.057533 5.516658 3.506228 3.762183 NA NA NA Nephropathy NA

97 CD74 6.747571 9.009517 7.77644 8.112901 NA NA NA Nephropathy NA

98 CD80 3.290634 4.533892 3.823706 3.98727 NA NA NA Nephropathy NA

99 CD9 8.579451 10.83787 9.685156 10.02759 Cardiovascular NA NA NA NA diseases 100 CDC123 8.173249 9.960141 9.028423 9.238614 Cardiovascular NA NA NA NA diseases 101 CDH1 9.288817 10.32485 9.709812 9.863577 NA NA NA Nephropathy NA

102 CDH2 6.731292 8.681773 7.565937 7.881566 NA NA NA Nephropathy NA

103 CDKAL1 7.280445 8.023111 7.601683 7.716681 Cardiovascular NA NA Nephropathy NA diseases 104 CDKN1A 7.186953 9.180886 8.186309 8.450832 NA NA NA Nephropathy NA

105 CDKN2A 5.651741 6.929843 6.239022 6.427538 Cardiovascular NA NA NA NA diseases 106 CETP 3.568777 4.869991 4.12883 4.303029 Cardiovascular NA Atherosclerosis NA NA diseases 107 CHI3L1 5.08217 9.610407 6.840369 7.417911 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 108 CHIT1 4.188622 5.859855 4.713938 4.912451 NA NA NA Nephropathy NA

109 CHN2 5.742582 7.115619 6.205129 6.411641 NA Retinopathy NA Nephropathy NA

110 CHPT1 7.178418 8.44049 7.653169 7.863334 NA NA NA Nephropathy NA

111 CISH 6.095593 7.187864 6.55167 6.726908 NA NA NA Nephropathy NA

112 CITED2 7.30687 8.637079 7.763787 7.934216 NA NA Atherosclerosis NA NA

113 CLCN5 5.561223 6.436938 6.081806 6.196036 NA NA NA Nephropathy NA

114 CLEC11 5.743796 6.509815 6.037674 6.163955 NA NA NA Nephropathy NA A 115 CLOCK 7.344909 8.231153 7.72799 7.867858 Cardiovascular NA NA NA NA diseases 116 CMA1 3.375247 4.177538 3.735456 3.86451 NA NA NA Nephropathy NA

117 CMC4 5.030452 6.46595 5.740629 5.950349 NA NA NA Nephropathy NA

118 CNDP2 7.961146 9.766564 9.010914 9.243126 NA NA NA Nephropathy NA

119 CNR1 3.57019 4.705907 3.83648 3.986002 NA Retinopathy NA Nephropathy Neuropathy

120 CNR2 4.648448 5.677457 5.137921 5.28924 NA NA NA Nephropathy Neuropathy

121 CNTF 5.693807 6.889395 6.059312 6.21408 NA NA NA NA Neuropathy

122 COG2 7.445474 8.475491 7.902622 8.059206 NA NA Atherosclerosis NA NA

130

123 COL8A1 3.498754 4.295824 3.809635 3.937994 NA NA NA Nephropathy NA

124 COL8A2 5.433936 6.288031 5.772902 5.892121 NA NA NA Nephropathy NA

125 COLEC1 4.263991 5.360563 4.75355 4.901607 NA Retinopathy NA NA NA 2 126 COMT 8.060841 8.818872 8.459022 8.584198 Cardiovascular NA NA NA NA diseases 127 CPVL 4.775671 6.320328 5.176689 5.408763 NA NA NA Nephropathy NA

128 CRH 4.519494 6.365187 5.176829 5.475994 NA NA NA NA Neuropathy

129 CRK 8.583945 9.368371 8.98452 9.102289 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 130 CRP 6.208159 12.01771 9.307169 10.21755 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 131 CST3 9.168127 10.37339 9.665162 9.856448 Cardiovascular NA NA NA NA diseases 132 CTGF 7.268862 10.04917 8.460252 8.906659 NA Retinopathy NA Nephropathy NA

133 CTSH 7.15825 10.36742 8.361289 8.837512 NA Retinopathy NA NA NA

134 CTSS 6.166506 8.112563 6.987263 7.270544 Cardiovascular NA NA NA NA diseases 135 CUBN 3.860427 5.021012 4.228278 4.376235 NA NA NA Nephropathy NA

136 CX3CL1 6.346161 8.922295 7.075077 7.384951 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 137 CX3CR1 3.31709 4.429201 3.781702 3.973643 NA NA NA Nephropathy NA

138 CXCL10 2.839327 7.406858 3.734993 4.430327 NA NA NA Nephropathy Neuropathy

139 CXCL11 3.105452 7.273866 4.015575 4.598144 NA NA NA Nephropathy NA

140 CXCL12 6.053052 9.037036 7.07481 7.521629 NA NA NA Nephropathy NA

141 CXCL5 6.226813 7.819397 6.803188 7.021166 NA NA Atherosclerosis Nephropathy NA

142 CXCL8 6.995423 11.37185 9.17981 9.833115 NA NA NA Nephropathy NA

143 CXCL9 3.00092 6.06802 3.774085 4.145291 NA NA NA Nephropathy NA

144 CYBA 6.25547 7.540607 6.780629 6.991865 NA NA Atherosclerosis Nephropathy NA

145 CYBB 4.815999 8.191129 6.210337 6.588962 NA Retinopathy NA NA NA

146 CYP1A1 4.361926 8.943436 6.589827 7.222522 Cardiovascular NA Atherosclerosis NA NA diseases 147 CYP24A1 3.040056 5.045018 3.523067 3.810634 NA NA NA Nephropathy NA

148 CYP2C19 3.451302 5.283172 4.009505 4.255743 NA Retinopathy NA NA NA

149 CYP2J2 5.422117 6.758017 6.039638 6.243787 Cardiovascular NA NA Nephropathy NA diseases 150 CYP7A1 2.712756 3.659578 3.048167 3.19265 Cardiovascular NA NA NA NA diseases 151 CYR61 5.911187 9.34597 7.495951 7.997575 NA Retinopathy NA NA NA

152 DCXR 8.313324 9.903136 9.107732 9.30854 NA NA NA Nephropathy NA

153 DDAH1 8.476329 10.10026 9.144486 9.353017 NA Retinopathy NA Nephropathy NA

154 DDIT3 6.78703 9.514712 7.686078 8.085476 Cardiovascular NA NA Nephropathy Neuropathy diseases 155 DES 5.794754 6.619821 6.13969 6.260355 NA NA NA Nephropathy NA

156 DGKH 5.330785 6.935983 5.921042 6.130869 NA NA NA Nephropathy NA

157 DHCR7 7.674491 9.634682 8.643783 8.923915 NA NA Atherosclerosis NA NA

158 DKK1 3.950056 6.279683 4.521418 4.807478 Cardiovascular Retinopathy NA Nephropathy NA diseases 159 DNMT1 6.419084 8.074612 7.204908 7.41346 NA NA NA Nephropathy NA

160 DPP4 6.052711 9.083102 7.329753 7.699375 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 161 EBF2 3.708895 4.929461 4.266322 4.448362 NA NA NA Nephropathy NA

162 EDN1 6.17579 8.489378 7.099059 7.477771 NA Retinopathy NA Nephropathy Neuropathy

163 EDNRA 5.14454 8.541548 7.030089 7.394144 NA NA NA Nephropathy NA

164 EGF 4.341294 7.246549 5.534613 5.963777 NA NA NA Nephropathy NA

165 EGFR 6.285312 8.09927 6.946393 7.24826 Cardiovascular NA NA Nephropathy NA diseases 166 EIF2AK3 6.363 8.410391 7.597278 7.858024 NA NA NA Nephropathy NA

131

167 EIF4EBP 7.514617 8.685158 7.971296 8.149135 NA NA NA Nephropathy NA 1 168 ELMO1 4.518496 6.881896 5.666957 5.970773 NA NA NA Nephropathy NA

169 ELN 6.07777 7.05949 6.61202 6.754219 NA NA Atherosclerosis NA NA

170 ENG 6.887448 8.996798 7.863599 8.122897 Cardiovascular Retinopathy NA NA Neuropathy diseases 171 ENPP1 6.800256 8.561457 7.485666 7.705293 NA NA NA Nephropathy NA

172 ENPP2 7.412698 12.13438 9.789506 10.4047 NA NA NA NA Neuropathy

173 ENTPD1 4.292772 5.651811 4.78746 4.99705 NA NA Atherosclerosis Nephropathy NA

174 EPO 5.328893 6.164527 5.709973 5.848103 NA Retinopathy NA Nephropathy Neuropathy

175 EPOR 4.76747 6.191535 5.522361 5.677778 NA NA NA Nephropathy NA

176 ERAP2 3.678479 7.495596 5.488432 6.184107 NA Retinopathy NA NA NA

177 ERBB2 5.94548 7.61241 6.682551 6.921145 Cardiovascular NA NA NA Neuropathy diseases 178 ERBB3 6.086027 8.502316 7.110309 7.456788 NA Retinopathy NA NA NA

179 ERBB4 4.619868 5.873302 4.962833 5.150346 NA NA NA Nephropathy NA

180 ERCC1 6.963811 7.758167 7.257394 7.387055 NA Retinopathy NA Nephropathy NA

181 ERCC4 6.389347 7.27623 6.710174 6.849385 NA Retinopathy NA Nephropathy NA

182 ESM1 5.478937 8.578923 6.923927 7.393244 NA NA NA NA Neuropathy

183 ESR1 3.808261 5.577275 4.360866 4.604794 NA NA NA Nephropathy NA

184 EXOSC7 6.428955 7.659833 7.053094 7.207589 NA NA NA Nephropathy NA

185 EZR 8.779405 10.63056 9.537198 9.82981 NA NA NA Nephropathy NA

186 F11 5.379631 7.993294 6.132994 6.534725 NA NA NA Nephropathy NA

187 F2R 5.033931 7.729457 6.455277 6.74617 NA NA NA Nephropathy NA

188 F8 4.621057 6.219762 5.208086 5.434538 NA NA NA NA Neuropathy

189 FABP1 3.280421 4.168381 3.603884 3.705006 Cardiovascular NA NA Nephropathy NA diseases 190 FABP2 2.594546 3.392811 2.867505 2.98657 NA NA NA Nephropathy NA

191 FABP4 3.392242 6.633247 4.237755 4.693364 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 192 FABP5 6.86865 10.64869 8.747295 9.188076 Cardiovascular NA Atherosclerosis NA NA diseases 193 FADS1 7.254244 9.086016 8.015253 8.30556 Cardiovascular NA NA NA NA diseases 194 FADS2 7.255493 9.464071 8.30873 8.6078 Cardiovascular NA NA NA NA diseases 195 FASN 6.724511 7.820372 7.17598 7.31915 NA NA NA Nephropathy NA

196 FFAR2 3.957086 5.302233 4.479843 4.642128 Cardiovascular NA NA NA NA diseases 197 FGF21 4.13501 5.148084 4.631106 4.773682 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 198 FGF23 4.528797 5.521782 4.88586 5.033797 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 199 FGFR1 6.893781 7.931872 7.2995 7.476738 NA NA Atherosclerosis NA NA

200 FKBP10 6.129984 7.777463 6.761213 7.001557 Cardiovascular NA NA NA NA diseases 201 FKBP2 8.281245 9.677059 8.855214 9.053329 NA NA Atherosclerosis NA NA

202 FKBP4 7.467306 9.343402 8.592776 8.792231 Cardiovascular NA NA NA NA diseases 203 FKBP8 7.656425 8.792724 8.190464 8.356331 Cardiovascular NA NA NA NA diseases 204 FMO3 3.691771 4.981452 4.035955 4.216527 NA NA Atherosclerosis NA NA

205 FMOD 5.68533 8.38392 6.96642 7.362361 NA NA Atherosclerosis NA NA

206 FN3K 5.717482 6.418158 5.993706 6.108796 NA NA NA Nephropathy NA

207 FOLH1 2.754358 3.874202 3.065697 3.202387 NA NA NA NA Neuropathy

208 FOS 7.595294 10.93582 8.581831 9.048576 NA NA NA Nephropathy NA

209 FOXA2 7.319661 8.561972 7.91424 8.095362 NA NA Atherosclerosis NA NA

210 FOXO1 8.410042 9.574146 8.846968 9.006537 NA NA Atherosclerosis NA NA

132

211 FOXO4 6.337444 7.403435 6.701955 6.870495 NA NA NA Nephropathy NA

212 FPR1 3.623352 4.387547 3.978596 4.101203 NA NA Atherosclerosis NA NA

213 FTO 8.496464 9.828927 9.071686 9.251011 Cardiovascular NA NA Nephropathy NA diseases 214 G6PD 7.726642 9.702927 8.939075 9.189053 Cardiovascular NA NA Nephropathy Neuropathy diseases 215 GAP43 5.340842 7.631917 6.260918 6.598883 NA NA NA NA Neuropathy

216 GAPDH 12.0187 13.51562 12.70327 12.91303 NA Retinopathy NA NA Neuropathy

217 GAS1 5.207286 5.945486 5.482459 5.619569 NA NA NA Nephropathy NA

218 GAS6 6.003948 8.031675 6.873023 7.158931 NA NA NA Nephropathy NA

219 GCG 13.06124 14.47651 13.62844 13.79865 NA NA NA Nephropathy NA

220 GCK 6.191312 7.632814 6.851321 7.071128 NA NA NA Nephropathy Neuropathy

221 GCKR 5.30048 7.441344 6.122326 6.442211 Cardiovascular NA NA NA NA diseases 222 GDF15 7.203711 9.707402 8.585423 8.956613 Cardiovascular NA NA Nephropathy NA diseases 223 GDNF 3.789539 4.683042 4.138829 4.247378 NA Retinopathy NA NA Neuropathy

224 GFAP 5.669418 6.444217 5.972146 6.0835 NA NA NA NA Neuropathy

225 GFPT1 9.463535 11.03827 10.24568 10.45221 NA NA NA Nephropathy NA

226 GFPT2 5.468664 8.675002 6.964401 7.339908 NA NA NA Nephropathy NA

227 GHR 3.857836 5.590326 4.632838 4.85533 NA NA NA Nephropathy NA

228 GHSR 5.384089 6.72177 5.88266 6.099639 NA NA NA Nephropathy NA

229 GIP 4.166991 5.188258 4.482224 4.626108 Cardiovascular NA Atherosclerosis NA Neuropathy diseases 230 GIPR 5.820448 7.132206 6.183742 6.364836 NA Retinopathy NA NA Neuropathy

231 GK 6.774701 8.703987 7.481739 7.735698 Cardiovascular NA NA NA NA diseases 232 GLO1 8.68896 10.26627 9.401125 9.634052 NA NA Atherosclerosis Nephropathy Neuropathy

233 GLP1R 6.648759 9.467692 7.758646 8.112138 Cardiovascular NA NA NA Neuropathy diseases 234 GLUL 7.529371 8.922469 8.144088 8.357873 Cardiovascular NA NA NA NA diseases 235 GNB3 4.949179 5.988381 5.345251 5.488128 NA NA NA Nephropathy NA

236 GPC5 3.855734 4.422213 4.056874 4.150996 NA NA NA Nephropathy NA

237 GPX1 6.919856 8.100493 7.657798 7.791418 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 238 GRB2 7.693888 8.631221 8.228975 8.369267 NA Retinopathy NA NA NA

239 GREM1 6.485164 9.937587 7.72471 8.283818 NA NA NA Nephropathy NA

240 GSTM1 5.694806 7.779757 6.348872 6.793531 NA Retinopathy Atherosclerosis Nephropathy NA

241 GSTT1 5.097991 8.932899 7.25724 7.946645 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 242 GYS1 6.123114 7.307126 6.686691 6.844041 Cardiovascular NA NA NA NA diseases 243 HCN2 5.871893 6.735188 6.25487 6.396012 NA NA NA NA Neuropathy

244 HDAC4 5.8142 6.630882 6.216589 6.349836 NA NA NA Nephropathy NA

245 HDAC9 5.482569 7.588353 6.492769 6.808949 NA NA Atherosclerosis NA NA

246 HFE 4.886181 6.536354 5.611955 5.843335 NA Retinopathy NA Nephropathy NA

247 HGF 4.140156 6.765722 5.056997 5.40024 NA NA Atherosclerosis Nephropathy Neuropathy

248 HHEX 7.365302 8.892824 8.045944 8.275637 Cardiovascular NA NA Nephropathy NA diseases 249 HIF1A 10.04833 12.14628 10.93061 11.2012 Cardiovascular NA NA Nephropathy NA diseases 250 HLA-A 11.59187 12.67504 12.09946 12.2724 NA NA NA Nephropathy NA

251 HLA- 4.676182 6.357043 5.188739 5.395239 NA NA NA Nephropathy NA DQA1 252 HMGA2 4.335447 5.395552 4.88015 5.00598 NA NA NA Nephropathy NA

253 HMGB1 5.856079 7.980591 6.756712 7.038125 Cardiovascular Retinopathy NA Nephropathy NA diseases 254 HMGCS2 4.453504 5.923084 4.903845 5.108705 NA NA NA Nephropathy NA

133

255 HMOX1 6.857136 10.86591 8.397179 8.918027 NA NA NA Nephropathy NA

256 HNF1A 5.971584 6.699546 6.222495 6.348476 NA NA NA Nephropathy NA

257 HNF1B 6.846215 9.164126 7.668468 8.032487 Cardiovascular NA NA NA NA diseases 258 HNF4A 6.464787 7.667897 6.869406 7.033577 Cardiovascular NA NA NA NA diseases 259 HP 2.285575 4.153059 2.915214 3.171962 Cardiovascular NA Atherosclerosis NA NA diseases 260 HPSE 4.724038 5.969427 5.271684 5.433507 NA NA NA Nephropathy NA

261 HRH1 4.553593 5.455604 4.923953 5.076847 NA NA NA NA Neuropathy

262 HRH2 4.017381 5.418973 4.638233 4.828138 NA NA NA NA Neuropathy

263 HSPA5 10.39404 12.47634 11.37909 11.74162 NA NA NA NA Neuropathy

264 HSPB1 9.768235 12.31259 11.22031 11.58867 NA NA NA Nephropathy NA

265 HSPG2 6.440788 7.820406 6.930214 7.154507 NA NA NA Nephropathy NA

266 HTR2A 3.079162 4.669476 3.451098 3.662111 NA NA NA Nephropathy NA

267 HYOU1 8.761843 10.49645 9.500101 9.74106 NA NA NA Nephropathy Neuropathy

268 ICAM1 6.105585 9.640253 7.493249 7.894825 NA NA Atherosclerosis Nephropathy NA

269 ID1 7.133131 9.507969 8.28365 8.62243 NA NA NA Nephropathy NA

270 IFNG 2.609698 3.551316 2.882909 3.014971 NA NA NA Nephropathy Neuropathy

271 IGF1 3.231142 4.230041 3.574626 3.721285 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 272 IGF1R 6.893016 8.644443 7.726342 7.94714 NA Retinopathy NA NA NA

273 IGFBP1 5.262718 6.190277 5.673118 5.81828 NA NA NA Nephropathy NA

274 IGFBP3 5.865573 9.771878 7.43885 7.919985 NA NA NA Nephropathy NA

275 IGFBP5 6.634156 10.42222 8.410461 8.974019 NA NA NA NA Neuropathy

276 IGFBP7 8.203574 9.982525 8.993227 9.271656 NA NA NA Nephropathy NA

277 IL10 3.636753 4.525785 3.978648 4.096998 NA NA NA Nephropathy Neuropathy

278 IL17A 4.755553 5.824204 5.272388 5.406857 NA Retinopathy NA Nephropathy NA

279 IL18 3.534295 6.823654 4.998782 5.546233 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 280 IL1B 4.808748 7.315603 5.446297 5.787045 Cardiovascular Retinopathy NA Nephropathy NA diseases 281 IL1RN 4.285275 8.272102 5.955644 6.523568 NA NA NA Nephropathy NA

282 IL4 2.885418 3.609407 3.188344 3.281511 NA NA NA NA Neuropathy

283 IL6 5.044484 8.339545 6.39285 6.918936 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

284 ILK 7.207243 9.073004 8.519745 8.740343 NA NA NA Nephropathy NA

285 INS 7.838968 10.628 8.923694 9.380401 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 286 IRAK1 7.260728 8.392073 7.822433 8.000296 NA NA NA NA Neuropathy

287 IRAK4 6.789622 7.764999 7.187313 7.319378 NA NA Atherosclerosis NA NA

288 IRS1 5.590383 7.306806 6.318139 6.593837 NA Retinopathy NA NA NA

289 IRS2 6.686949 8.064343 7.27614 7.461259 NA NA Atherosclerosis Nephropathy Neuropathy

290 ITGA2 8.227243 10.30152 9.18604 9.565849 NA Retinopathy NA NA NA

291 ITGAM 4.524739 5.505539 4.911504 5.039297 NA Retinopathy NA Nephropathy NA

292 ITGB3 6.307131 8.874598 7.663761 8.031861 NA Retinopathy NA NA NA

293 JAK2 5.816735 6.65502 6.127762 6.263191 NA NA NA Nephropathy NA

294 KCNQ1 5.586036 7.21092 6.101841 6.300924 NA NA NA Nephropathy NA

295 KDM1A 7.907011 8.781308 8.419868 8.534431 NA Retinopathy NA NA NA

296 KL 5.000198 7.186712 6.116387 6.436464 NA NA NA Nephropathy NA

297 KLF10 8.230973 9.940366 8.88471 9.178275 NA NA NA Nephropathy NA

298 KLF6 6.96144 8.670092 7.651768 7.903524 NA NA NA Nephropathy NA

134

299 L1CAM 4.730814 5.672764 5.153693 5.308607 NA Retinopathy NA NA NA

300 LAMC1 8.203372 9.925996 9.064621 9.338799 NA NA NA Nephropathy NA

301 LAP3 7.081925 8.571561 7.684798 7.936793 NA NA NA Nephropathy NA

302 LDLR 8.556983 9.832477 9.0834 9.287842 Cardiovascular NA Atherosclerosis NA NA diseases 303 LEP 4.587201 5.7374 5.032271 5.188397 NA NA Atherosclerosis NA Neuropathy

304 LIMK2 6.670893 8.854799 7.484775 7.791207 NA NA NA Nephropathy NA

305 LMNA 7.334763 8.588414 7.857012 8.045844 NA NA NA Nephropathy NA

306 LPA 3.726253 5.054173 4.07361 4.238775 Cardiovascular NA Atherosclerosis NA NA diseases 307 LPL 4.724742 6.409465 5.279878 5.487909 Cardiovascular NA Atherosclerosis Nephropathy Neuropathy diseases 308 LPO 4.347465 5.42351 4.746003 4.897389 NA Retinopathy NA NA NA

309 LRP2 3.712982 4.352337 3.984384 4.072789 NA NA NA Nephropathy NA

310 LTB4R2 5.463352 6.40413 5.868884 6.014583 NA Retinopathy NA NA NA

311 MAFB 6.623638 10.45195 8.565738 9.099796 Cardiovascular NA Atherosclerosis NA NA diseases 312 MALT1 6.029764 7.229432 6.469447 6.637191 NA NA NA Nephropathy NA

313 MAP3K5 6.368667 8.195403 7.14936 7.397854 Cardiovascular NA NA Nephropathy NA diseases 314 MAPK1 8.804348 9.489672 9.116879 9.220902 NA NA NA Nephropathy Neuropathy

315 MAPK14 5.943666 7.990941 7.228594 7.476667 NA NA NA Nephropathy NA

316 MAPK7 5.679625 6.449877 6.00596 6.128697 NA Retinopathy NA NA NA

317 MBL2 3.56957 4.421771 3.872141 4.005112 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 318 MBP 5.951479 7.247769 6.476624 6.679344 NA NA NA NA Neuropathy

319 MC4R 3.69709 4.752665 4.142969 4.297006 Cardiovascular NA NA Nephropathy NA diseases 320 MCAM 6.077771 7.747471 6.919335 7.181693 NA NA NA Nephropathy NA

321 MEP1B 3.752598 6.176938 4.469736 4.817192 NA NA NA Nephropathy NA

322 MIF 8.90835 10.42472 9.496014 9.69392 NA NA Atherosclerosis Nephropathy Neuropathy

323 MME 3.867278 5.242339 4.236603 4.451015 NA NA NA NA Neuropathy

324 MMP14 7.21439 9.499042 8.470071 8.777765 NA NA NA Nephropathy NA

325 MMP16 3.751548 6.432417 4.799433 5.133238 NA NA NA Nephropathy NA

326 MMP2 6.260641 9.242072 7.393608 7.775976 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 327 MMP24 4.997601 6.119018 5.367662 5.500567 NA NA NA Nephropathy NA

328 MMP9 5.402565 9.075488 6.532352 7.036706 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 329 MOK 4.64693 5.813943 5.109687 5.259637 NA NA Atherosclerosis Nephropathy NA

330 MPO 4.244505 5.243872 4.665816 4.799395 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 331 MRPL28 7.159857 8.028273 7.519792 7.656233 NA Retinopathy NA NA NA

332 MSH2 5.491979 7.73404 6.622063 6.880342 Cardiovascular NA NA NA NA diseases 333 MTHFR 5.729182 6.785515 6.245814 6.386114 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

334 MTOR 6.583359 7.535155 7.059669 7.207347 NA NA NA Nephropathy NA

335 MYD88 7.128617 8.165647 7.607309 7.775589 NA NA NA Nephropathy NA

336 MYH9 9.143044 10.87819 9.817733 10.09881 NA NA NA Nephropathy NA

337 MYO5C 6.445113 8.457323 7.485142 7.768044 NA Retinopathy NA NA NA

338 NAGLU 7.192142 8.032129 7.537136 7.642423 Cardiovascular Retinopathy NA NA NA diseases 339 NAMPT 9.093671 11.76899 10.18048 10.60043 Cardiovascular NA NA NA NA diseases 340 NCALD 5.860602 7.952021 6.89761 7.193688 NA NA NA Nephropathy NA

341 NCF1 5.102183 6.11684 5.630238 5.775006 NA NA NA Nephropathy NA

342 NCF2 5.556171 8.63583 6.836269 7.24598 NA NA NA Nephropathy NA

135

343 NDUFS3 8.83425 9.862712 9.291279 9.452941 NA NA NA Nephropathy NA

344 NEDD4L 7.739169 9.352776 8.270226 8.526282 NA NA NA Nephropathy NA

345 NFE2 4.023546 5.038558 4.414097 4.549624 NA NA NA Nephropathy NA

346 NFE2L2 8.678621 10.0984 9.339504 9.573149 NA Retinopathy NA Nephropathy Neuropathy

347 NFKBIA 8.456522 11.43312 9.53135 9.919928 NA NA NA Nephropathy NA

348 NGB 5.255671 6.249853 5.675274 5.82937 NA Retinopathy NA NA NA

349 NGF 5.157172 6.322563 5.835233 6.002035 NA NA NA Nephropathy Neuropathy

350 NGFR 5.540536 6.468694 5.986942 6.125298 NA NA NA NA Neuropathy

351 NLRP3 3.825102 4.964303 4.185338 4.321957 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 352 NOD2 3.980463 4.850192 4.385287 4.514709 NA NA NA Nephropathy NA

353 NOS1 4.245142 5.163897 4.607309 4.762366 NA Retinopathy NA Nephropathy Neuropathy

354 NOS2 4.451131 5.387819 4.776091 4.910748 NA Retinopathy NA Nephropathy NA

355 NOS3 5.061648 5.969002 5.42729 5.558966 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 356 NOV 6.117462 7.465545 6.568162 6.78019 NA NA NA Nephropathy NA

357 NOX1 2.705882 3.577076 3.233411 3.341739 NA NA NA Nephropathy NA

358 NOX3 3.443496 4.241583 3.746993 3.860278 NA NA NA Nephropathy NA

359 NOX4 3.695898 5.104119 4.23981 4.42136 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 360 NPHS1 4.639657 5.59259 5.017941 5.159243 NA NA NA Nephropathy NA

361 NPPA 4.242794 5.305779 4.693083 4.86313 Cardiovascular NA NA NA NA diseases 362 NPY 5.247879 8.811616 6.494886 7.012091 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

363 NPY2R 3.693825 4.748329 4.188768 4.34032 Cardiovascular NA NA NA NA diseases 364 NPY5R 2.81551 3.960911 3.172443 3.340625 Cardiovascular NA NA NA NA diseases 365 NQO1 7.702587 9.704589 8.627791 8.890987 Cardiovascular NA Atherosclerosis NA NA diseases 366 NR1H3 5.536296 6.531872 6.070844 6.215471 NA NA NA Nephropathy NA

367 NR3C2 5.7628 7.724306 6.731675 7.00001 Cardiovascular NA NA NA NA diseases 368 NRF1 6.042229 6.939641 6.327861 6.460483 NA NA NA NA Neuropathy

369 NSA2 9.036022 10.65328 9.700379 9.969836 NA NA NA Nephropathy NA

370 NTF3 4.060985 5.03135 4.464737 4.621646 NA NA NA NA Neuropathy

371 NTS 2.879269 5.86972 3.641035 4.099959 Cardiovascular NA NA NA NA diseases 372 NUCB2 8.961542 10.72314 9.821162 10.06661 Cardiovascular Retinopathy NA NA NA diseases 373 ONECUT 6.503822 7.663383 6.928751 7.105734 NA NA NA Nephropathy NA 1 374 OSM 4.606798 5.545298 5.042833 5.194625 NA NA NA Nephropathy NA

375 OXT 5.712305 6.733742 6.206649 6.376198 Cardiovascular NA NA NA NA diseases 376 P2RX2 4.885137 5.899374 5.386573 5.533581 NA NA NA NA Neuropathy

377 P2RX3 4.430967 5.502808 4.905141 5.039017 NA NA NA NA Neuropathy

378 P2RY1 5.419603 7.439317 6.204049 6.472618 NA NA NA NA Neuropathy

379 P2RY2 5.331878 6.175595 5.672549 5.794998 NA NA NA NA Neuropathy

380 PAK6 5.883452 7.107015 6.229008 6.390764 NA NA NA NA Neuropathy

381 PARL 8.615786 10.20964 9.038952 9.245068 Cardiovascular NA NA Nephropathy NA diseases 382 PARP1 7.935135 9.21781 8.660926 8.823429 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 383 PC 6.101272 7.017821 6.472994 6.607003 NA NA NA Nephropathy NA

384 PDE5A 5.956975 7.224554 6.561995 6.726459 NA NA NA Nephropathy Neuropathy

385 PDGFB 5.628403 6.705094 6.072598 6.233125 NA NA NA Nephropathy NA

386 PDGFD 6.006682 9.416036 7.16688 7.653204 NA NA Atherosclerosis NA NA

136

387 PDGFRB 6.628082 9.897229 8.397077 8.789889 NA NA NA Nephropathy NA

388 PDHX 7.464198 8.755331 8.016192 8.226281 NA Retinopathy NA NA NA

389 PDK1 6.165543 7.494598 6.630752 6.810764 NA NA NA Nephropathy NA

390 PDPK1 6.815123 7.987368 7.336393 7.515477 NA NA NA Nephropathy NA

391 PEBP1 8.309872 9.729799 8.8939 9.096877 NA NA NA Nephropathy NA

392 PECAM1 6.501702 9.501788 8.183178 8.566705 NA NA NA NA Neuropathy

393 PFKFB2 6.524165 9.801189 8.163623 8.546174 NA NA NA Nephropathy NA

394 PGF 5.081092 7.186809 6.03775 6.3064 Cardiovascular NA NA NA NA diseases 395 PHACTR 4.541452 5.681281 4.905913 5.047241 Cardiovascular NA NA NA NA 1 diseases 396 PICK1 6.167552 7.129838 6.668609 6.788114 NA NA NA Nephropathy NA

397 PIGF 5.373095 8.245856 7.082324 7.404565 NA Retinopathy NA NA NA

398 PIK3CA 6.588746 8.036533 7.278599 7.502438 NA NA NA Nephropathy NA

399 PIP 3.58512 5.281988 4.010047 4.250771 NA NA NA Nephropathy NA

400 PLA2G2 4.732957 8.646907 5.593034 6.117512 NA NA Atherosclerosis NA NA A 401 PLIN1 4.973857 5.952812 5.44437 5.581747 Cardiovascular NA NA NA NA diseases 402 PLIN2 6.883843 9.198134 7.89102 8.200023 Cardiovascular NA NA NA NA diseases 403 PLN 2.458013 3.297381 2.685393 2.809202 Cardiovascular NA NA NA NA diseases 404 PLTP 5.682172 8.433721 6.876467 7.282023 NA NA Atherosclerosis NA NA

405 PLXDC1 4.962321 7.020678 5.628149 5.9363 NA Retinopathy NA NA NA

406 PMP22 6.41936 8.508967 7.413172 7.681167 NA NA NA NA Neuropathy

407 PNPLA3 3.870898 4.953714 4.40281 4.54461 Cardiovascular NA NA NA NA diseases 408 POLR2D 7.086057 8.065937 7.522611 7.65462 NA Retinopathy NA NA NA

409 POMC 5.405103 6.706675 5.857922 6.006732 Cardiovascular NA NA NA Neuropathy diseases 410 PON1 3.645955 6.348019 4.522599 4.918231 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy diseases 411 PON2 8.271633 10.23618 9.060341 9.360016 NA NA Atherosclerosis Nephropathy NA

412 PON3 6.807587 9.045182 7.496226 7.818642 Cardiovascular NA Atherosclerosis NA NA diseases 413 POSTN 4.187011 8.897312 5.926586 6.633909 NA Retinopathy NA Nephropathy NA

414 PPARA 5.616513 6.605086 6.108526 6.240914 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 415 PPARG 4.322781 5.372208 4.674453 4.840563 NA Retinopathy Atherosclerosis Nephropathy NA

416 PPARGC 4.8022 7.805453 5.946056 6.328829 Cardiovascular Retinopathy NA Nephropathy Neuropathy 1A diseases 417 PPIA 11.29533 12.56775 12.03395 12.18254 Cardiovascular NA NA Nephropathy NA diseases 418 PPY 7.891634 12.49304 9.73693 10.44702 NA NA NA NA Neuropathy

419 PRCP 8.358737 9.707837 9.001165 9.218355 Cardiovascular NA Atherosclerosis Nephropathy NA diseases 420 PRDX1 9.880004 11.35763 10.46577 10.69327 Cardiovascular NA NA NA NA diseases 421 PRDX2 6.34727 7.331178 6.74338 6.886742 Cardiovascular NA NA NA NA diseases 422 PRDX4 8.636303 10.68229 9.376259 9.664282 Cardiovascular NA NA NA NA diseases 423 PRDX6 9.059776 10.38375 9.60754 9.792792 Cardiovascular NA NA NA NA diseases 424 PRKAA1 7.713973 8.798373 8.245485 8.407447 NA NA NA Nephropathy NA

425 PRKCB 4.022397 5.050127 4.44326 4.58315 NA NA NA Nephropathy Neuropathy

426 PRKCE 6.639593 7.76263 7.109908 7.288448 NA NA NA Nephropathy NA

427 PRKG1 4.538258 6.023545 5.252744 5.463945 NA NA NA NA Neuropathy

428 PRMT2 7.015998 8.36764 7.742869 7.904617 NA NA Atherosclerosis NA NA

429 PROC 4.688692 5.730313 5.192963 5.339024 NA NA NA Nephropathy NA

430 PROM1 6.050203 9.715766 7.946478 8.456809 NA NA NA NA Neuropathy

137

431 PSIP1 5.400411 6.77355 6.011393 6.208813 NA Retinopathy NA NA NA

432 PSMA6 9.223577 10.93493 9.94504 10.22479 Cardiovascular NA NA Nephropathy NA diseases 433 PSMD9 6.581447 7.861925 7.066305 7.253283 NA Retinopathy NA Nephropathy Neuropathy

434 PTEN 9.031649 10.1606 9.52292 9.6959 NA NA NA Nephropathy Neuropathy

435 PTGDS 5.919224 7.150331 6.387287 6.576257 NA NA Atherosclerosis Nephropathy NA

436 PTGER1 6.269284 7.352117 6.686908 6.845782 NA NA NA Nephropathy NA

437 PTGER4 5.627773 6.666049 6.10349 6.278332 NA NA NA Nephropathy NA

438 PTGES 6.091547 8.130919 6.798285 7.034737 NA NA NA Nephropathy NA

439 PTGS2 5.22027 10.06647 7.46449 8.109937 Cardiovascular Retinopathy NA Nephropathy Neuropathy diseases 440 PTH 2.283987 2.994741 2.487872 2.57962 Cardiovascular NA NA Nephropathy NA diseases 441 PTH1R 4.953284 5.797752 5.233787 5.366793 NA NA NA Nephropathy NA

442 PTPN1 7.683906 8.696845 8.095682 8.244155 Cardiovascular NA NA Nephropathy NA diseases 443 PTX3 3.72642 5.740135 4.428589 4.732714 NA Retinopathy Atherosclerosis Nephropathy NA

444 RAF1 7.604045 8.768648 8.152688 8.365425 NA Retinopathy NA Nephropathy NA

445 RARRES2 6.632291 9.275629 7.664502 8.079989 Cardiovascular NA NA NA NA diseases 446 RBP1 8.187046 9.945821 8.895929 9.152073 NA Retinopathy NA NA NA

447 RBP4 7.226873 11.53248 9.415379 9.985103 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 448 RCAN1 7.036098 8.773228 7.684338 7.954722 NA NA NA Nephropathy NA

449 REG1A 11.9984 13.89816 13.20001 13.45937 NA NA NA Nephropathy NA

450 RELA 7.678473 8.650487 8.028177 8.1907 NA Retinopathy NA Nephropathy NA

451 REN 3.954249 6.177583 4.601458 4.820735 Cardiovascular NA Atherosclerosis NA NA diseases 452 RETN 5.476913 6.674893 6.040954 6.214567 Cardiovascular NA Atherosclerosis NA NA diseases 453 RGN 4.795572 6.893178 5.795481 6.128115 NA NA NA Nephropathy NA

454 RHO 4.040092 5.159708 4.60043 4.74366 NA Retinopathy NA NA NA

455 RHOA 10.66289 12.03513 11.11818 11.29545 NA NA NA NA Neuropathy

456 RHOD 6.273564 7.584372 6.961932 7.158578 NA NA NA Nephropathy NA

457 RNLS 5.914914 6.899912 6.430274 6.561989 Cardiovascular NA NA NA NA diseases 458 ROCK2 7.545058 8.839715 8.129737 8.351803 NA NA Atherosclerosis NA NA

459 RPS12 8.487384 9.988175 9.087037 9.285519 NA NA NA Nephropathy NA

460 RPS6 10.96746 12.71562 11.46255 11.70265 NA NA NA Nephropathy NA

461 RPS6KA6 5.850932 7.680341 6.627604 6.866977 NA NA NA NA Neuropathy

462 RREB1 6.719287 7.690975 7.110351 7.257612 NA NA NA Nephropathy NA

463 RTN1 6.264348 9.836952 7.935119 8.413134 NA NA NA Nephropathy NA

464 S100A12 3.368753 4.249483 3.722786 3.850849 Cardiovascular Retinopathy NA NA NA diseases 465 SARDH 5.111908 6.077144 5.543405 5.69307 NA Retinopathy NA NA NA

466 SCARB1 5.965894 7.373713 6.570651 6.749348 NA NA Atherosclerosis NA NA

467 SELE 3.921902 5.824413 4.494282 4.709492 NA NA NA Nephropathy NA

468 SEMA3A 4.632073 6.808839 5.289056 5.571473 NA NA NA Nephropathy NA

469 SERPINB 4.257898 7.887034 5.556266 6.145138 NA NA NA Nephropathy NA 7 470 SERPINE 8.416546 10.97733 9.534055 9.900594 NA NA NA Nephropathy NA 1 471 SERPINF 5.927255 9.26202 6.989604 7.424658 NA Retinopathy NA Nephropathy Neuropathy 1 472 SERPINF 5.012138 5.940701 5.412191 5.547713 NA NA NA Nephropathy NA 2 473 SFI1 5.9021 6.64078 6.136772 6.25879 NA NA NA Nephropathy NA

474 SGK1 6.507139 9.061464 7.362165 7.725668 NA NA NA Nephropathy NA

138

475 SGK2 5.848894 7.483244 6.597098 6.819462 NA NA NA Nephropathy NA

476 SGK3 6.314414 7.557791 6.803276 6.992668 NA NA NA Nephropathy NA

477 SHBG 5.053329 5.803742 5.400624 5.525917 Cardiovascular NA NA NA NA diseases 478 SIGLEC1 4.693044 5.615098 5.086919 5.224329 NA NA NA Nephropathy NA

479 SIRT1 7.224015 8.369153 7.709098 7.884586 Cardiovascular Retinopathy Atherosclerosis NA NA diseases 480 SIRT6 6.480653 7.106164 6.721174 6.809766 NA NA NA Nephropathy NA

481 SLC12A3 5.124724 6.029615 5.537424 5.695103 NA NA NA Nephropathy NA

482 SLC22A6 4.889567 5.805121 5.240574 5.376202 NA NA NA Nephropathy NA

483 SLC2A1 7.440159 8.957625 7.960052 8.176094 Cardiovascular NA NA Nephropathy NA diseases 484 SLC2A2 5.071308 8.824044 6.780893 7.307948 NA NA NA Nephropathy NA

485 SLC2A3 6.34559 8.922224 7.420614 7.712115 NA NA NA NA Neuropathy

486 SLC2A4 4.797668 5.712173 5.199671 5.31663 Cardiovascular NA NA Nephropathy Neuropathy diseases 487 SLC30A1 3.610646 4.69944 4.030699 4.199674 NA NA NA NA Neuropathy 0 488 SLC5A2 5.222702 6.186067 5.700465 5.848419 Cardiovascular NA NA NA NA diseases 489 SLC9A1 6.583836 7.395026 6.826782 6.956892 NA NA NA Nephropathy NA

490 SMAD1 6.37753 7.384286 6.838306 6.968245 NA NA NA Nephropathy NA

491 SMAD7 6.192454 7.775237 6.784303 6.98177 NA NA NA Nephropathy NA

492 SMPD1 8.028689 9.699908 8.804614 9.028059 NA Retinopathy NA NA NA

493 SOCS1 5.665158 6.69917 6.173016 6.326001 NA NA NA Nephropathy NA

494 SOCS2 6.571322 7.738913 6.913473 7.08551 NA NA NA Nephropathy NA

495 SOCS3 5.707063 7.336168 6.42676 6.654874 NA Retinopathy NA Nephropathy NA

496 SOD1 10.17198 11.46106 10.73692 10.93409 NA Retinopathy NA Nephropathy NA

497 SOD2 8.607791 10.86723 9.475209 9.791109 NA Retinopathy NA NA Neuropathy

498 SORBS2 7.199735 9.320601 8.105238 8.404178 NA NA NA Nephropathy NA

499 SOX9 6.189182 8.212943 6.933803 7.18761 NA NA NA Nephropathy NA

500 SPARC 7.639934 10.78716 9.505954 9.940406 NA Retinopathy NA Nephropathy NA

501 SPON2 5.913719 8.30732 6.931115 7.263683 NA NA NA Nephropathy NA

502 SPP1 8.73499 12.77001 11.24036 11.84283 Cardiovascular Retinopathy NA Nephropathy NA diseases 503 SRC 6.462119 7.335743 6.830386 6.978994 NA NA NA Nephropathy NA

504 SREBF1 6.767537 8.240543 7.327579 7.523019 NA NA NA Nephropathy Neuropathy

505 SRGN 6.63691 9.305748 7.934233 8.269364 NA Retinopathy NA NA NA

506 SST 11.51368 14.16819 13.01608 13.32903 NA Retinopathy NA Nephropathy NA

507 STAT1 8.469675 10.44247 9.340571 9.605416 NA NA NA Nephropathy NA

508 STAT3 9.746936 11.21956 10.52057 10.71964 NA Retinopathy NA Nephropathy NA

509 STAT5A 5.891746 6.678283 6.22332 6.366532 NA NA NA Nephropathy NA

510 STEAP4 4.597594 8.142268 6.447962 6.909974 NA NA Atherosclerosis NA NA

511 STK11 6.83622 7.703467 7.177404 7.294495 NA NA NA Nephropathy NA

512 SUMO4 5.194058 5.999554 5.525294 5.646387 Cardiovascular NA NA Nephropathy NA diseases 513 TACR1 3.836133 4.930361 4.399538 4.549389 Cardiovascular NA NA NA NA diseases 514 TCF7L2 6.205977 7.904519 7.029471 7.2589 Cardiovascular Retinopathy Atherosclerosis Nephropathy NA diseases 515 TF 3.679675 5.840784 4.422219 4.655257 NA NA NA Nephropathy NA

516 TFAM 6.759233 8.026718 7.437678 7.591405 NA NA NA NA Neuropathy

517 TGFB1 6.097698 8.333745 7.206157 7.47991 Cardiovascular NA NA Nephropathy NA diseases 518 TGFBR1 7.66048 9.128978 8.229219 8.431569 NA NA NA Nephropathy NA

139

519 TH 5.218327 6.094057 5.641503 5.778634 NA Retinopathy NA NA Neuropathy

520 THBD 6.721315 8.826448 7.574424 7.891028 NA NA NA Nephropathy NA

521 THBS1 8.371773 10.42556 9.151468 9.46318 NA Retinopathy NA Nephropathy NA

522 THBS2 6.246176 9.763315 7.887481 8.270583 NA NA NA Nephropathy NA

523 TIMM44 7.20553 7.902107 7.502258 7.611805 NA NA NA Nephropathy NA

524 TIMP1 10.95816 13.04453 12.02133 12.32369 NA Retinopathy NA NA NA

525 TIMP2 8.452982 10.06846 9.233167 9.484675 NA NA NA Nephropathy NA

526 TIMP3 6.418169 9.234416 7.7784 8.155894 NA Retinopathy Atherosclerosis Nephropathy NA

527 TKT 8.682998 10.15349 9.412573 9.646203 NA NA NA Nephropathy Neuropathy

528 TLR2 4.84016 6.242408 5.258239 5.468365 NA NA NA Nephropathy NA

529 TLR4 4.470309 5.994236 5.095224 5.308028 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

530 TM6SF2 5.4634 6.396255 5.867412 6.020964 Cardiovascular NA NA NA NA diseases 531 TNFAIP8 5.785536 8.019693 6.708425 7.042313 NA NA NA Nephropathy NA

532 TNFRSF1 4.565209 7.565058 5.899707 6.295353 Cardiovascular Retinopathy Atherosclerosis Nephropathy Neuropathy 1B diseases 533 TNFRSF1 5.234715 6.305758 5.634238 5.79188 NA NA NA NA Neuropathy B 534 TPM1 6.422187 9.753771 8.030175 8.478974 Cardiovascular NA NA NA NA diseases 535 TRAF6 7.400638 8.148855 7.64007 7.730516 NA NA NA NA Neuropathy

536 TRH 4.653244 5.961827 5.263465 5.432879 NA NA NA NA Neuropathy

537 TRIB3 6.647507 8.482467 7.311954 7.558947 Cardiovascular NA NA Nephropathy NA diseases 538 TRPA1 2.767856 4.439048 3.247022 3.442126 NA NA NA NA Neuropathy

539 TRPC1 5.416058 7.807593 6.207985 6.50392 NA NA NA Nephropathy NA

540 TRPC6 3.769252 4.946671 4.153617 4.322007 NA NA Atherosclerosis Nephropathy NA

541 TRPV1 5.364432 6.303632 5.694158 5.82673 NA NA NA NA Neuropathy

542 TRPV4 5.280818 6.426378 5.651627 5.817006 NA NA NA Nephropathy NA

543 TSC1 6.346274 7.549761 6.900791 7.055701 NA NA NA Nephropathy NA

544 TSC2 6.657554 7.596449 7.042263 7.183652 NA NA NA Nephropathy NA

545 TSC22D1 7.355605 9.1714 8.147801 8.41011 NA NA NA Nephropathy NA

546 TSPO 6.445236 7.594036 6.938737 7.108209 NA NA NA NA Neuropathy

547 TUBB3 7.255197 8.539009 7.769856 7.952304 NA Retinopathy NA NA NA

548 TXN 9.341125 11.5919 10.37048 10.68182 Cardiovascular NA Atherosclerosis NA NA diseases 549 TXNIP 9.39563 11.18584 10.3339 10.58852 NA Retinopathy Atherosclerosis Nephropathy NA

550 UCP1 3.948079 4.991388 4.323711 4.459239 NA Retinopathy NA NA NA

551 UCP2 5.052007 7.051594 5.934015 6.20229 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

552 UMOD 4.836015 5.673129 5.118954 5.245895 NA NA NA Nephropathy NA

553 UNC13A 6.258209 8.277601 7.208914 7.509947 NA NA NA NA Neuropathy

554 UNC13B 6.633488 8.210137 7.547195 7.750942 NA NA NA Nephropathy NA

555 UNC5B 6.676624 8.064631 7.228805 7.411237 NA NA NA Nephropathy NA

556 USF2 8.111609 8.906486 8.462358 8.580234 NA NA NA Nephropathy NA

557 UTRN 6.425714 7.888701 7.021422 7.239623 NA NA NA Nephropathy NA

558 UTS2 2.406646 3.742343 2.737555 2.868789 NA Retinopathy Atherosclerosis NA NA

559 VCAM1 6.107822 10.08191 7.966388 8.562914 Cardiovascular NA Atherosclerosis NA NA diseases 560 VDAC1 7.342533 9.014614 8.039211 8.267105 NA NA NA Nephropathy NA

561 VDAC2 6.034752 7.437609 6.839964 7.032675 NA NA NA Nephropathy NA

562 VDR 5.490064 6.546529 5.95602 6.115277 Cardiovascular Retinopathy NA Nephropathy NA diseases

140

563 VEGFA 8.181311 9.737204 8.771085 9.011178 NA Retinopathy Atherosclerosis Nephropathy Neuropathy

564 VEGFC 5.602254 6.855943 6.123735 6.299976 NA Retinopathy NA NA NA

565 VIP 3.195293 7.950949 4.264623 4.870004 NA NA NA NA Neuropathy

566 VWF 4.8167 6.915072 5.526094 5.842594 Cardiovascular NA NA Nephropathy Neuropathy diseases 567 WFS1 6.345062 8.355871 7.407632 7.684582 NA NA NA Nephropathy NA

568 WT1 4.63376 5.572973 5.133484 5.257814 NA NA NA Nephropathy NA

569 XBP1 9.912085 11.46902 10.71225 10.91701 NA NA NA Nephropathy NA

570 XIAP 6.603852 7.550895 6.970157 7.099799 NA NA NA NA Neuropathy

571 XRCC1 6.698334 7.75072 7.171484 7.317249 Cardiovascular Retinopathy NA NA NA diseases 572 ZEB2 4.650296 6.669671 5.419002 5.67261 NA NA NA Nephropathy NA

573 ZNF236 5.526454 6.219309 5.772702 5.867013 NA NA NA Nephropathy NA

141

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