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Chromatin Conformation Links Distal Target Genes to CKD Loci

Maarten M. Brandt,1 Claartje A. Meddens,2,3 Laura Louzao-Martinez,4 Noortje A.M. van den Dungen,5,6 Nico R. Lansu,2,3,6 Edward E.S. Nieuwenhuis,2 Dirk J. Duncker,1 Marianne C. Verhaar,4 Jaap A. Joles,4 Michal Mokry,2,3,6 and Caroline Cheng1,4

1Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands; and 2Department of Pediatrics, Wilhelmina Children’s Hospital, 3Regenerative Medicine Center Utrecht, Department of Pediatrics, 4Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, 5Department of Cardiology, Division Heart and Lungs, and 6Epigenomics Facility, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands

ABSTRACT Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chro- mosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, iden- tifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.

J Am Soc Nephrol 29: 462–476, 2018. doi: https://doi.org/10.1681/ASN.2016080875

CKD is a condition marked by loss of kidney func- functional annotation and explanation of these loci tion, which can lead to ESRD and is associated with a remain an issue. Currently, the functional annota- dramatic increase in cardiovascular disease–related tion of GWAS data is mainly conducted by linking morbidity and mortality.1 On the basis of the latest report of the Center for Disease Control and Pre- Received August 15, 2016. Accepted September 9, 2017. vention (2007–2014), over 15% of the United States M.M.B. and C.A.M. contributed equally to this work. M.M. and population is affected by CKD, and the numbers are C.C. contributed equally to this work. expected to rise. CKD incurs substantial rising Published online ahead of print. Publication date available at medical costs in the United States, with similar de- www.jasn.org. velopments observed globally. Over the last decade, Correspondence: Dr. Caroline Cheng, University Medical Center the findings of multiple genome-wide association Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. studies (GWASs) have established common DNA Email: [email protected] variants as genetic risk factors for CKD.2,3 However, Copyright © 2018 by the American Society of Nephrology

462 ISSN : 1046-6673/2902-462 J Am Soc Nephrol 29: 462–476, 2018 www.jasn.org BASIC RESEARCH susceptibility loci by spatial proximity to the nearest gene.4 For Significance Statement example, well known single-nucleotide polymorphisms (SNPs) that are associated with CKD include SNPs annotated Genome-wide association studies (GWASs) have identified a num- with ALMS1 and UMOD. ALMS1 is required for medullar ber of genetic regions correlated with development of CKD, but collecting duct ciliogenesis,5 whereas UMOD is involved in establishing causality remains challenging. This study applies a new fl approach to GWAS interpretation: to complement classic annota- the inhibition of calcium oxalate crystallization in renal u- tion on the basis of linear spatial proximity, the principle of tran- ids6 and has an evolutionary role in protection from urinary scriptionaldysregulationisusedtoidentifysiteswhereCKD-associated tract infections.7 Because these SNPs are located in coding variation colocalizes with DNA regulatory elements. The study de- regions of genes with important renal protective functions, scribestheidentificationof304candidategenesthatphysicallyinteract it is conceivable that the genetic variation marked by these with regulatory elements that colocalize with 39 common variants associated with CKD. Future studies will be required to verify the SNPs affects both genes, contributing to CKD pathogenesis. findings of this screening pipeline, but the method could help to de- For many of the CKD-associated susceptibility loci that are not termine the causal roles that common variants play in complex dis- directly located in or near protein coding regions, the causal eases, such as CKD. contribution to disease etiology is far less straightforward. New insights brought by epigenetic research have revealed the prevalence of DNA regulatory elements (DREs), such as target gene expression, leading to disease or other phenotypes enhancers and repressors, located in both coding- and non- (Figure 1, C and D). This was shown previously for the SNP protein-coding DNA regions (Figure 1A).8 These DREs play a rs12913832, which was shown to modulate human pigmentation crucial role in regulating gene expression in a cell-specific by affecting the enhancer regulation of the OCA2 promoter.10 manner. Enhancer elements regulate transcription of their Systematic mapping of the target genes of DREs that overlap target genes through three-dimensional (3D) chromatin in- with known CKD-associated SNPs could greatly improve our un- teractions with transcriptional start sites (TSSs) (Figure 1B). derstanding of the complex genetics of CKD. Importantly, DREs can regulate expression levels of gene targets Here, we used self-transcribing active regulatory region over a distance up to thousands of kilobase pairs,9 far exceeding the sequencing (STARR-seq) to evaluate the potential effect of current standard distance for GWAS annotation. Common genet- CKD-associated genetic variation on transcriptional regula- ic variation in DREs could be a causative factor in dysregulation of tion.Inaproofofprincipleapproach,weclonedputativeDREs located on the same linkage disequilibrium (LD) block as the CKD-associated SNP rs11959928 from 20 donors in STARR-seq reporter plasmids. This approach enabled us to study the effect of all variants found on this susceptibility region in the donor pool on enhancer activity in primary human renal proximal tubular epithelial cells (HRPTECs), human renal glomerular endo- thelial cells (HRGECs), and the human embryonic kidney cell line HEK293a. The findings of this experiment illustrated how regulatoryfunctioncouldbeaffectedbycom- mon small variants, thereby highlighting the relevance of studying downstream target genes of DREs overlapping with disease- associated susceptibility regions to add an additional layer to post-GWAS analysis. Subsequently, we used circular chromo- some conformation capture sequencing (4C-seq) to identify putative candidate genes for CKD by examining 3D interac- Figure 1. Genetic variation in DREs could be a causative factor in dysregulation of tions between DREs that colocalize with distal target gene expression. (A) Many of the susceptibility loci that are not located in CKD susceptibility loci and their target protein coding regions overlap with DREs, such as enhancers and repressors. (B) DREs play a crucial role in regulating gene expression in a cell-specific manner by modulating genes. This allowed us to study long-range 3D chromatin interactions and increasing spatial proximity of DREs with TSSs, thereby regulation of target gene promoters by regulating transcription of genes on a nonlinear DNA scale. (C) Distal transcriptional crosslinking the folded and interacting activity of DREs could be compromised by (D) genetic variation (represented by co- DRE segments followed by two restriction- localization with disease-associated SNP). ligation steps of the DNA strands and

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Figure 2. STARR-seq analysis illustrates the effect of CKD-associated genetic variation on transcriptional regulation. (A) The STARR-seq reporter principle is on the basis of a reporter plasmid containing a minimal promotor followed by a cloned candidate enhancer se- quences. The activity of each enhancer is reflected by its ability to transcribe itself. ORF, Open Reading Frame. (B) Putative DREs, identified by H3K4Me1, H3K27Ac, and DNAse clusters (human umbilical vein endothelial cells are in blue and human epidermal keratinocytes are in pink; overlap is shown in purple; adapted from USCS genome browser), located on the haploblock marked by CKD- associated SNP rs11959928 (I–III) were cloned into the STARR-seq plasmid from 20 individual donors. (C) The library of STARR-seq plasmids was transformed in HRGECs, HRPTECs, and HEK293a followed by RNA-seq of the produced enhancer RNA strands. Shown in replicate is the percentage of the reference allele in the input library, the percentage of the reference allele in cellular transcribed RNA, and the D between the prevalence in the library and transcribed RNA (found in region I).

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DNA sequencing. Because transcriptional regulation is sequences on the haploblock with its original frequency in the celltypespecificand becauseCKD pathogenesis is associated library (Supplemental Table 2). Via this approach, one particular with reduced GFR as a result of tubulointerstitial fibrosis11 as region containing five variants was found to be strongly affected well as loss of peritubular and glomerular capillaries,12,13 we by allele-specific activity in all three examined cell types (Figure conducted the 4C-seq in HRPTECs and HRGECs. Chromatin 2C). Four of these variants had a reference allele frequency of interactions were studied in these primary cells from healthy 45.2%–74.8% in the library input, but virtually only the refer- donors to create an overview of genes interacting with CKD ence alleles were transcribed in all three cell types. The other susceptibility loci. We conducted a systematic screen of 39 allele had a wild-type penetrance of 31.8%–36.5% in the library putative regulatory elements that colocalize with previously input, but its frequency was strongly reduced in the transcribed reported susceptibility regions for CKD. This led to the iden- RNA. This example illustrates that disease-associated SNPs not tification of 304 target genes that are potentially transcription- only may affect gene coding sequences but might also affect the ally affected by these CKD-associated SNPs. This study shows, transcriptional regulation of DRE target genes. for the first time a direct interaction between CKD-associated common variant regions and the promoter regions of CKD- 4C-Seq Leads to Discovery of New Target Genes for associated target genes. Although additional functional studies CKD-Associated SNPs are needed to determine the exact mechanism of action, Building on the illustrative STARR-seq findings, 39 CKD- in this form, our data present an extensive overview of poten- associated susceptibility loci that colocalize with DREs were tial target genes for the previously reported CKD-associated studied in HRGECs and HRPTECs to identify the target genes SNPs, providing new gene candidates for hypothesis-driven of putative DREs.2,3 Activity of these DREs was assessed in renal future studies. epithelium and fetal renal tissue for HRPTECs and microvascu- lar endothelium for HRGECs on the basis of DNase hypersen- sitivity and H3K4me3 chromatin immunoprecipitation data RESULTS (Supplemental Table 3). Of the 39 studied loci, six colocalize only with active DREs in renal epithelium, five colocalize only STARR-Seq Directly Shows the Potential of Genetic with active DREs in microvascular endothelium, and 28 loci Variation to Affect Regulation of Gene Expression colocalize with active DREs in both renal epithelium and mi- Toillustrate the effect of genetic variation on regulatory activity crovascular endothelium. For the discovery of target genes of of DREs as an additional layer to GWAS interpretation, the these regulatory elements, the TSSs that interacted with these STARR-seq reporter setup was used to test the influence of loci were examined in HRPTECs and HRGECs using 4C-seq common genetic variants colocalizing with possible DREs po- (Figure 3, A–F). Sixty-seven chromatin interaction datasets sitionedon the haploblock marked by the CKD-associated SNP were generated in twofold, of which only the replicated chro- rs11959928. The STARR-seq reporter assay is on the basis of a matin interactions were considered as candidate genes. These reporter plasmid containing a minimal promoter followed by candidate genes were filtered per cell type for expression in an incorporated candidate enhancer sequence.14 The activity that specific cell type using in-house and public expression of each enhancer is reflected by its ability to induce the pro- datasets (Figure 3G). This led to the discovery of 304 CKD moter activity, leading to RNA transcription of the enhancers target genes, of which 199 were found in HRGECs (Figure 4, sequence (Figure 2A). The advantage of this approach over Supplemental Table 4) and 229 were found in HRPTECs (Fig- luciferase reporter assays is that STARR-seq allows parallel ure 5, Supplemental Table 5). Among the 199 target genes (and thus, “high-throughput”) assessment of all genomic var- interacting in HRGECs and 229 target genes interacting in iation in the enhancer regions located on this specifichaplo- HRPTECs, 124 were identified in both cell types (Figure block, because the effect of a variant on enhancer strength is 3G). These 304 candidate genes all fulfilled the following three reflected by its relative prevalence in transcribed RNA com- criteria. (1)TheTSSofthecandidategenecolocalizeswitha 2 pared with its prevalence in the pool of reporter plasmids. significant 4C-seq signal (P,10 8) within 5 kbp. (2)TheSNP Putative DREs located on the haploblock marked by the or any other SNP in LD (r.0.8) colocalizes with active regu- CKD-associated SNP rs11959928 (Figure 2B), containing at latory regions. (3) The candidate gene is expressed in the cell least three potential regulatory regions (I–III) as illustrated by types of interest (reads per kilobase million reads sequenced H3K4Me1, H3K27Ac, and DNAse clusters in human umbilical [RPKMs] .21 and probe intensity .6formicrovascular vein endothelial cells and human epidermal keratinocytes (adapt endothelium RNA-seq data and HRPTECs microarray data, ed from USCS genome browser), were cloned from 20 individ- respectively).15 TheTSSsofthemajorityofcandidategenes ual donors into one combined reporter library (Supplemental found with circular chromosome conformation capture (4C; Table 1). This library was transformed in HRGECs, HRPTECs, both expressed and nonexpressed) were positioned within and HEK293a (the latter cell type was used an additional con- 500 kbp from the lead SNP position (88% in HRGECs and trol) followed by sequencing of the produced enhancer-derived 84% in HRPTECs), but occasionally, interacting genes were RNA as well as the library itself, enabling us to compare tran- found over 1000 kbp from the SNP locus (seven in HRGECs scription frequency of eachvariable allele located in the enhancer and 23 in HRPTECs) (Supplemental Figure 1).

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Figure 3. 4C-seq was used to study chromatin interactions, leading to the discovery of 304 CKD target genes in total. The 3D chromatin conformation of the DREs was studied in detail on the basis of the 4C template, which was generated by (A) fixing the chromatin structure, followed by (B) enzymatic (DpnI restriction enzyme) digestion of the fixed chromatin. (C) The digested chromatin was ligated into circular fragments in a diluted environment, after which (D) the chromatin was decrosslinked. (E) The circular DNA molecules followed another round of enzymatic (CvIQI restriction enzyme) digestion and ligation, after which the 4C-seq library was prepared with primers that target sequences in close proximity of the CKD susceptibility loci. (F) This library was sequenced to identify genes that were physically interacting with CKD susceptibility loci. (G) The 4C analysis was initially performed on 48 viewpoints on the basis of CKD-associated SNPs, of which, in total, 39 colocalized with active DREs on the basis of mapping with DNase hypersensitivity or H3K04me3 ChIP-seq datasets (33 in HRGECs and 34 in HRPTECs with partial overlap of SNPs). Of these 39 studied viewpoints, only 36 (31 in HRGECs and 34 in HRPTECs with partial overlap of viewpoints) were interacting with a total of 304 target genes with validated expression in the assessed cell types (overlap indicated in the Venn graph). These 304 genes were subsequently processed for genetic annotation to renal failure–associated traits in the OMIM database and the MGI database in addition to eQTL analysis in the GTEx portal database and pathway analysis using IPA software.

Genetic Annotation of Candidates Picked Up by genes in mice caused direct renal failure–related traits, includ- 4C-Seq in the Online Mendelian Inheritance in Man and ing albuminuria (ALMS1, MPV17,andSCARB2), abnormal the Mouse Genome Informatics Shows Link with CKD renal filtration rate (SLC14A1), and glomerular sclerosis We evaluated if the identified candidates were associated with (CCNI, MPV17,andVEGFA) (Table 2). Of the 23 renal failure CKD using the Online Mendelian Inheritance in Man (OMIM) trait–associated target genes found with the MGI, 13 are lo- and the Mouse Genome Informatics (MGI) databases. The cated entirely on a different haploblock than the 4C viewpoint OMIM database is a catalog of human genetic disorders that (Table 2, white unpatterned mark). connects rare gene variants with phenotype. Weestablished the overlap of our HRPTECs and HRGECs gene lists with the genes Expression Quantitative Trait Loci Analyses Reveal retrieved from the OMIM Morbid Map by searching for the Genotype-Dependent Expression of CKD keywords “kidney,”“renal,” and “nephro.” Monogenetic de- Candidate Genes fects in five CKD candidate genes were directly correlated A candidate gene with an expression level that is significantly with a renal disease phenotype, of which two are completely correlated with co-occurrence of an SNP is likely to be tran- located on a different haploblock than the 4C viewpoint (Table scriptionally regulated by a DRE affected by the SNP.These loci 1, white unpatterned mark). The MGI database contains mu- that contribute to variation in gene expression levels, called rine phenotypic information of mutant alleles. Analysis re- expression quantitative trait loci (eQTL), are identified using vealed that monogenetic silencing of 23 of the CKD candidate GWAS and RNA-seq data of the target organ. To date, no large

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Figure 4. Analysis of chromatin interactions of CKD susceptibility loci that colocalize with regulatory elements using 4C-seq led to the discovery of 199 CKD target genes in glomerular endothelial cells. (A) Chromatin interactions were studied in cultured HRGECs to define endothelial target genes of CKD susceptibility loci that colocalize with active regulatory elements. (B) Of a total of 33 replicated 4C datasets, on the basis of CKD susceptibility loci that colocalize with active regulatory elements, 30 interacted with at least one target gene that was expressed in endothelium, which led to the identification of 199 CKD target genes in total. Studied SNPs are displayed ordered on position followed by haploblock information (vertical stripe, gene partly inside the SNP haploblock; white, gene completely outside the SNP haploblock; horizontal stripe, gene completely inside the SNP haploblock; black, SNP haploblock inside the gene; dot pattern, SNP not in the defined haploblock) and the SNP-TSS distance in kilobase pairs. ns, Nonsynonymous SNP. *SNP solely as- sociated with serum creatinine (eGFR); **SNP solely associated with serum urate; ***SNP solely associated with BUN. genome-wide eQTL data of the human kidney have been pub- expression-matched data of 449 donors for which eQTL analysis lished that allow adequate analysis of all CKD-associated was conducted in 44 nonrenal tissues, which is large enough to SNPs.16 To evaluate if the expression levels of the CKD candi- stratify most of the individual CKD SNPs and wild-type alleles date genes are affected by CKD-associated SNPs, we used the assessed in our study. Of the 39 CKD-associated susceptibility Genotype-Tissue Expression (GTEx) database. Although the loci, 25 were annotated in the GTEx. These 25 SNPs were sig- GTEx so far only contains kidney-specific expression data of 26 nificantly correlated with the expression of 54 genes, of which 48 genotyped donors, which does not reach the GTEx threshold for physically interacted with the 4C-seq input loci (data not eQTL analysis (.70), the database does include genotype- and shown). Of these 48 captured target genes, 38 were actually

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Figure 5. Analysis of chromatin interactions of CKD susceptibility loci that colocalize with regulatory elements using 4C-seq led to the discovery of 229 CKD target genes in renal proximal tubular epithelial cells. (A) Chromatin interactions were studied in cultured HRPTECs to define epithelial target genes of CKD susceptibility loci that colocalize with active regulatory elements. (B) Of a total of 34 4C datasets, on the basis of CKD susceptibility loci that colocalize with active regulatory elements, 34 interacted with at least one target gene that was expressed in HRPTECs, which led to the identification of 229 CKD target genes in total. Studied SNPs are displayed ordered on position followed by haploblock information (vertical stripe, gene partly inside the SNP haploblock; white, gene completely outside the SNP haploblock; horizontal stripe, gene completely inside the SNP haploblock; black, SNP haploblock inside the gene; dot pattern, SNP not in the defined haploblock) and the SNP-TSS distance in kilobase pairs. ns, Nonsynonymous SNP. *SNP solely associated with serum creatinine (eGFR); **SNP solely associated with serum urate; ***SNP solely associated with BUN. expressed in HRPTECs and/or HRGECs, and they included shows the ability of the studied elements to establish an ten genes located on a completely different haploblock than SNP-dependent expression pattern of captured target genes the CKD-associated SNP (Table 3, white unpatterned mark). in the 4C-seq approach. Interesting eQTL target genes also Thus, although the lack of genotype-kidney expression data- picked up by 4C-seq include the solute carriers SLC28A2 and sets prohibited us to study these eQTL in renal tissue, this SLC30A4 (rs2453533) and in relation to renal fibrosis, the

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Table 1. Overlapping genes in 4C-seq retrieved genes and CKD-associated genes in the OMIM

genes encoding for the secreted proteases CTSS and CTSK proof of principle approach for rs11959928 using STARR-seq. (rs267734) (Figure 6). (2) CKD-associated loci interact with promoter regions of target genes via 3D chromatin folding. By taking this DNA Pathway Analyses Reveal Potentially Disrupted regulatory information into account in GWAS annotation, we Mechanisms and Regulators in CKD found many novel CKD candidate genes. (3)MultipleSNP Other than studying individual loci and interacting genes, we target genes sets can be distinguished. (4) The identified target used Ingenuity Pathway Analysis (IPA; QIAGEN) to determine genes can be linked to CKD in human and murine disease the pathways in which the CKD candidate genes are involved. databases (the OMIM and the MGI). (5) eQTL analysis re- In both HRGECs and HRPTECs, the 4C candidate genes veals that expression of many target genes is genotype depen- were most significantly enriched in biosynthesis pathways dent. (6) HRGEC- and HRPTEC-derived target genes share (Supplemental Tables 6 and 7), including the superpathway the trans, trans-farnesyl diphosphate biosynthesis pathway of geranylgeranyl diphosphate biosynthesis (P,0.001 and as a common molecular mechanism. Combined, our data P,0.001, respectively) and the trans, trans-farnesyl diphos- annotated multiple new genes to previously reported CKD- phate biosynthesis pathway (P,0.001 and P=0.001, respectively) associated SNPs and provided first time evidence for direct (Figure 7, A and B). Interestingly, both molecular pathways are interaction between these common variant regions and their linked to the mevalonate pathway (Supplemental Figure 2). targets. Future studies are now required to pinpoint causal 4C-seq identified FDPS and PMVK (rs2049805) as well as genetic variant(s) at each locus, allowing a deeper under- IDI1 and IDI2 (rs10794720) as candidate genes in relation to standing of their associated disease mechanisms and their the mevalonate pathway in CKD. relevance in kidney disease. In addition, IPAwas used to identify upstream regulators of Previously reported GWASs for CKD-associated SNPs used which the target genes were over-represented among the CKD classic annotation on the basis of spatial proximity principles to candidate genes. Targets of the transcription factors ATF6 identify affected target genes.4 This includes annotation of (P=0.002 and P,0.001) and FOXO4 (P,0.001 and SNPs on the basis of location in coding regions or close prox- P,0.001) were significantly enriched in the CKD candidates imity of TSS (taking into account that the average promotor is in both HRGECs and HRPTECs, respectively, whereas targets 100- to 1000-bp long) but also takes into consideration that of HNF4a were only enriched in HRPTECs (P=0.04). It was these SNPs could be markers for less common variants in gene previously shown that HNF4a was crucial for establishing and bodies. Using STARR-seq analysis, variants in LD with the maintaining transcriptional enhancer elements in the renal CKD-associated SNP rs11959928 were shown to affect activity proximal tubule and that suboptimal DNA binding properties of a DRE in an allele-specific manner, emphasizing that not among others led to transcriptional dysregulation of a variety only protein coding variants but also, variants located in of solute carriers.17 Interestingly, from publically available mi- regulatory regions could be at the basis of development or croarray data (NCBI Gene Expression Omnibus accession no. progression of complex diseases. Therefore, we examined GSE66494),18 all three transcription factors were found to be the 3D folded state of the chromatin by 4C-seq to list genes significantly upregulated in renal biopsies from patients with that interact with DREs in LD with CKD-associated SNPs. CKD compared with healthy controls (Figure 7C), suggesting This approach led to the identification of 304 CKD candidate that these three factors are potentially key regulators in CKD. genes, of which many are not directly located near the asso- ciated susceptibility loci. Most enhancers are located several hundred kilobase pairs and sometimes, even 1000 kbp from DISCUSSION their target genes.9 In our study, the majority of the SNPs are located between 100 and 500 kbp from the target genes’ The main findings of the study are listed (1) CKD-associated TSS, supporting the idea that the interactions observed in variation can affect transcriptional regulation as shown in a the 4C-seq approach are enhancer-target gene interactions.

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Table 2. Overlapping genes in 4C-seq retrieved genes and CKD-associated genes in the MGI

The effect of common genetic variants in DREs is relatively 585 kbp (rs13246355), 337 kbp (rs2049805), and 702 kbp low19; therefore, it is unlikely that the CKD-associated SNPs (rs13538) from the CKD-associated SNP, respectively. In addi- in these elements will result in creating new or completely tion, validation of the 4C-seq approach was provided by analysis ablating 3D DRE-gene interactions. Rather, dysregulation in in the OMIM dataset, which showed that multiple target genes theexpressionofageneprofile that is part of the regulation were linked to CKD-associated traits in human. For example, ofkidneyhomeostasisinhealthyindividualsismorelikely MUC1 and PKD2 were identified by 4C-seq as a result of the the contributing factor in CKD etiology. The 4C-seq ap- interaction of their promoter regions with regulatory do- proach helps us to interpret genetic variants as a determin- mains that colocalize with rs2049805 and rs2725220, re- ing factor of the expression levels of interacting targets in the spectively. MUC1 encodes the protein mucin-1, which is a pathogenesis of CKD. membrane anchored mucoprotein involved in providing a By overlapping our 304 CKD target genes with datasets protective barrier against pathogens. A frameshift mutation provided by the OMIM and the MGI, we confirmed their in MUC1, leading to a novel stop codon, induced medullar relevance to kidney disease: Analysis with the MGI database cystic kidney disease type 1 (MIM: 158340).24 PKD2 en- showed that mice deficient for the CKD candidate genes codes the polycystin-2 protein, which is involved in renal MPV17, CCNI, ASH1L,andSLC4A5 suffer from renal failure– calcium transport and calcium signaling. Mutations in the related traits.20–23 These genes are located 185 kbp (rs1260326), gene, leading to loss of function, cause the formation of

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Table 3. Overlapping genes in 4C-seq retrieved genes and eQTL genes derived from the GTEx portal

fluid-filled cysts, eventually leading to progressive destruc- and their corresponding 4C-seq–captured genes in (human) tion of the renal parenchyma (MIM: 173910),25 butitwas CKD. recentlyalsoshowntobeinvolvedinbranchingandnet- Evidence for the transcription regulatory function of the work formation of lymphatic endothelium, which plays a CKD-associated SNP regions was provided by GTEx database crucial role in renal function.26,27 Such examples illustrate analysis. Many of the CKD susceptibility loci were eQTL, the potential relevance of the candidate genes identified by showing a significant correlation between SNP genotypes 4C-seq for renal function and provide clear evidence for the and expression level of linked target genes in a variety of tissues. functional association between the investigated SNP regions These eQTL target genes include CTSS and CTSK coding for

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protein reabsorption, because inhibition of 3-hydroxy-3-methylglutaryl CoA reductase in the mevalonate pathway leads to reduced prenylation of GTP binding proteins in- volved in receptor-mediated endocytosis, eventually resulting in proteinuria.30 Simi- larly, altered levels of prenylation of RhoA affect eNOS activity in endothelial cells, re- sulting in imbalance of ROS levels and con- tributing to the endothelial dysfunction reported in CKD onset.31 In our systemic approach, other than the noncoding variants, we also included two nonsynonymous SNPs (SNPs in gene cod- ing regions that alter protein sequence: rs1260326 in GCKR and rs13538 in NAT8) that were among the studied re- gions. Presumably, the affected genes are involved in the associated disease pheno- type. Especially reports on NAT8 activity in association with kidney disease seem convincing.32–34 However, it was previ- ously shown that DREs can also be located in coding regions,35 and it remains of in- terest that, by 4C-seq, we found interac- tions of this locus with TSSs of multiple other genes, of which the expression levels Figure 6. Expression levels of 4C-seq captured genes are correlated with the asso- according to GTEx are significantly associ- ciated CKD SNP. (A) The expression level of solute carriers SLC28A2 and SLC30A4 is ated with the occurrence of the variant. The lower in the presence of the heterozygous (Het) and homozygous alternative (Homo Alt) alleles (rs2453533) compared with the homozygous reference (Homo Ref) “wild- incorporation of regulatory information type” allele (P values ,0.001 and ,0.001, respectively; adjusted from the GTEx provides an additional layer in post- portal). (B) Similarly, the expression levels of the secreted proteases CTSS and CTSK GWAS data to aid in our interpretation of are lower in the presence of the Het and Homo Alt alleles (rs267734) compared with these GWAS datasets but certainly does not the Homo Ref allele (P values ,0.001 and ,0.001, respectively; adjusted from the replace the candidate genes identified on GTEx portal). SNP-target gene pair P values were on the basis of matrix eQTL analysis the basis of spatial proximity, such as in linear regression mode as described by the GTEx consortium.39 NAT8. Along the same lines, several SNPs associated with a single trait were included. cathepsin S and K, respectively, and both are downregulated Several SNPs are solely associated with serum creatinine in the presence of rs267734. Cathepsins are potent proteases, (eGFR). Although these SNPs might be causally associated and the negative correlation between rs267734 and cathepsin with CKD, they might also affect creatinine production/secre- S and K expression might be relevant in relation to renal tion independent of renal function. rs91119 is only associated fibrosis, which is critically involved in CKD progression. In a with serum cystatin C (eGFR), and it is located directly within bleomycin lung fibrosis model, it was shown that cathepsin the CST locus. Again, this SNP does not necessarily have to be K–deficient mice had more severe lung fibrosis than wild- causally associated with CKD but could also be involved in the type mice.28 Furthermore, it was observed that pharmacologic dynamics of cystatin C production. The same is true for SNPs inhibition of cathepsin activity in mice with unilateral ureteral solely associated with serum urate or BUN, although the au- obstruction–induced renal fibrosis led to a worse outcome,29 thors who identified SNPs associated with the latter group had indicating that reduced expression of cathepsin S and K in the corrected for nonrenal factors.3 presence of rs267734 could contribute to CKD. In conclusion, taking the 3D structure of chromatin into Pathway analysis showed enrichment of 4C-seq captured account, we have identified 304 putative CKD candidate genes genes in multiple biosynthesis pathways involved in the gen- of DREs that colocalize with CKD susceptibility loci. In this eration of isoprenoid pyrophosphates. Interestingly, this en- hypothesis generation–driven approach, we present a new richment was observed in HRGECs and HRPTECs, although method of GWAS interpretation on the basis of DRE target with different identified target genes per cell type. Isoprenoid gene identification by 4C analysis that complements the pyrophosphates are indispensable for renal proximal tubular classic methods of candidate gene identification. In

472 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 462–476, 2018 www.jasn.org BASIC RESEARCH

Figure 7. CKD candidate genes are enriched in pathways of biosynthesis, microangiopathy, and molecular transport. IPA revealed that CKD candidate genes in both (A) HRGECs and (B) HRPTECs were most enriched in biosynthesis pathways, including the superpathway of geranylgeranyl diphosphate biosynthesis and the trans, trans-farnesyl diphosphate biosynthesis pathway. These pathways play crucial roles in protein reuptake in HRPTECs. P values were calculated by a right-tailed Fisher exact test. (C) Upstream regulators, identified by IPA on the basis of the enrichment of their target genes in the 4C-seq–derived candidates, were significantly higher when expressed in renal biopsy specimens from patients with CKD (derived from GSE66494). P values were calculated by a nonparametric t test. *P,0.05; **P,0.001. addition, incorporation of the adapted STARR-seq method with candidate variants (minor allele frequency .0.03) within the up- or downstream of the 4C pipeline would further narrow susceptibility locus were PCR amplified (primers in Supplemental down the identification of causal variants in DNA regulatory Table 1), equimolarly pooled, and cloned into pSTARR-seq_human function and help us to greatly expand our understanding of vector (Addgene). The library complexity was verified by dilution the role that common low-risk variants play in the onset of series after transformation, and it was estimated to contain 50,000 complex diseases, such as CKD. individual reporter clones; 40 million cells were placed in 1600 ml electroporation buffer (Bio-Rad) supplemented with 120 mg (HEK293a) or 240 mg (HRPTECs and HRGECs) library, after which CONCISE METHODS electroporation mixture was divided over 16 2-mm electroporation cuvettes (Bio-Rad) followed by electroporation with a square wave Cell Culture (110 V/25 ms for HEK293a and 125 V/20 ms for HRPTECs and Primary HRGECs (derived from human donor cell biobank Sciencell) HRGECs) using Gene Pulser Xcell (Bio-Rad). After electroporation, and HRPTECs (Sciencell) were cultured on fibronectin- and gelatin- cells were seeded in normal culture medium for 24 hours followed by coated plates on ECM medium (supplemented with the endothelial RNA extraction using the RNeasy isolation kit (QIAGEN). The poly- cell growth kit and penicillin/streptomycin; Sciencell) and EpiCM adenylated fraction of the total RNA was isolated using Dynabeads medium (supplemented with the epithelial cell growth kit and Oligo dT 25 (Thermo Fisher). The reporter-specific cDNA was syn- penicillin/streptomycin; Sciencell), respectively. Human embry- thesized and amplified according to standard STARR-seq proto- onic kidney cells (HEK293a) were cultured on gelatin-coated plates cols.14 The amplified cDNA was subsequently fragmented (Covaris on DMEM (Lonza) supplemented with 10% FCS (Gibco) and 100 S2 ChIP seq program: power peak 40 and duty factor 5 cycle/burst U/mlpenicillin/streptomycin(Lonza).Allcellswereculturedin5% 200) and cleaned followed by sequencing library preparation using fl CO2 at 37°C. The experiments with primary cells were conducted NEXT ex ChIP-Seq library prep kit for Illumina sequencing. The with cells at passage 3. libraries were sequenced on the Illumina NextSeq500 platform to produce 75-bp-long single-end reads. STARR-Seq Reporter Assay DNA from 20 individual donors was isolated from whole blood ob- 4C-Seq tained from the Mini Donor Service (positive approval from the med- The 4C template was prepared as previously described.36 In summary, ical ethics committee of the University Medical Center Utrecht; 10 million HRGECs or HRPTECs (both primary cells from healthy protocol no. 07/125) via salt precipitation. Regions (approximately donors) were fixed in 2% formaldehyde, after which cells were lysed. 1200 bp in size) containing DNase hypersensitivity sites overlapping The chromatin of the lysed cells was digested with the four-base

J Am Soc Nephrol 29: 462–476, 2018 4C Analysis of CKD-Associated SNPs 473 BASIC RESEARCH www.jasn.org cutter DpnI (NEB) followed by ligation in a heavily diluted environ- serum medium (EBM-2 medium supplemented with 0.5% FCS) us- ment with T4 ligase (Roche). The ligated samples were decrosslinked ing the RNeasy isolation kit. Poly(A) Beads (NEXTflex) were used to followed by a second digestion with the four-base cutter CvIQI isolate polyadenylated mRNA, from which sequencing libraries were (NEB). Next, samples were ligated once more in a diluted environ- made using the Rapid Directional RNA-seq Kit (NEXTflex). Libraries ment, after which the chromatin was purified. The efficiency of each were sequenced using the Nextseq500 platform (Illumina), produc- digestion and ligation step was validated on agarose gels. Viewpoints ing single-end reads of 75 bp. Reads were aligned to the human were selected on the basis of the CKD susceptibility loci found in the referencegenomeGRCh37usingSTAR,version2.4.2a.Picard GWASs of Okada et al.3 and Köttgen et al.2 If multiple SNPs were AddOrReplaceReadGroups (v1.98) was used to add read groups to found in a genomic region spanning ,20 kbp, only the SNP with the the BAM files, which were sorted with Sambamba v0.4.5, and tran- lowest P value was selected as the viewpoint. To study the chromatin script abundances were quantified with HTSeq-count, version interactions of CKD-associated susceptibility loci with 4C, primers 0.6.1p1, using the union mode. Subsequently, RPKMs were calcu- were designed for each viewpoint as described previously.36 Briefly, lated with edgeR RPKM function. Genes were accepted as expressed primers were designed within a 5-kbp window surrounding the if probe intensity was .6orlog2(RPKM) was .21 in HRPTECs and CKD-associated SNP. Forward primers were designed in the first re- microvascular endothelium, respectively. striction site, and the reversed primers were designed close to the second restriction site (,100 bp), with a minimum distance of 300 Haploblock Localization bp between the forward primer and the reversed primer. In the case Haploview (Broad Institute) was used to download LD plots 500 kb that no suitable primers could be designed on the basis of these spec- up- and downstream from CKD-associated SNPs (pairwise compar- ifications, either the window size surrounding the SNP was increased isons of markers ,2000 kbp apart). From these LD plots, haplo- to 10 kbp or the distance between the forward and reversed primers blocks, containing CKD-associated SNPs, were extracted to evaluate was reduced (Supplemental Table 8). 4C libraries were sequenced target gene localization in relation to the CKD-associated suscepti- using the NextSeq500 platform (Illumina), producing single-end bility region. reads of 75 bp. The raw sequencing reads were then demultiplexed on the basis of viewpoint-specific primer sequences. Reads were trim- Genetic Annotation with the OMIM medto16basesandmappedtoanin silico–generated library of The OMIM morbid map database was used to find mutant alleles that fragment ends (fragends) neighboring all DpnI sites in human ge- were associated with CKD. CKD-associated traits were mapped on the nome (NCBI37/hg19) using the custom Perl scripts.37 No mis- basis of the phenotype category queries “renal,”“kidney,” and matches were allowed during the mapping. The reads mapping to “nephro.” ThegenesetfoundintheOMIMwasusedtoidentify only one possible fragend were used for additional analysis. known CKD-associated genes in the list of genes generated via the 4C-seq approach. Target Gene Identification First, the number of covered fragends within a running window of k Genetic Annotation with the MGI fragends throughout the whole chromosome was calculated (only the The MGI database was used to find monogenic mutant murine alleles viewpoint’s chromosome was taken into account). The k was set sep- that led to CKD-related traits. A data file containing the “approved arately for every viewpoint, and therefore, it contained, on average, 20 gene name” and the “mouse genome database ID” was downloaded covered fragends in the area around the viewpoint (6100 kbp). Sec- from the HUGO Gene Nomenclature Committee to identify the mu- ond, we compared the number of covered fragends in each running tated murine genes in the MGI database that led to CKD-related window with the theoretical random distribution. The windows with traits. CKD related traits were mapped on the basis of the following significantly higher numbers of covered fragends compared with ran- phenotype categories: abnormal kidney morphology, abnormal 2 dom distribution (P,10 8 on the basis of binominal cumulative kidney angiogenesis, urine abnormalities, blood abnormalities, glo- distribution function; R pbinom) were considered as a significant merulus abnormalities, renal tubules abnormalities, podocyte abnor- 4C signal. The following criteria were defined for the identification malities,kidneycysts,abnormalrenalfiltration, and other kidney of the candidate genes. (1) The TSS colocalizes with a significant 4C- related traits. The gene set found in the MGI was used to identify 2 seq signal (P,10 8) within 5 kbp. (2) The CKD-associated SNP or known CKD-associated genes in the list of genes generated via the other variant in LD colocalizes with at least one of the published 4C-seq approach. datasets that represents candidate regulatory sequences (Supplemen- tal Table 3) in a similar cell type as that from which the 4C signal was. eQTL Study in the GTEx Portal (3) The candidate gene has been validated to be expressed by mRNA The GTEx portal database containing data on eQTL in 449 genotyped datasets. donors with expression data in 44 different tissues was used to list genes that significantly correlated in their expression with Identification of Gene Expression CKD-associated SNPs that colocalized with active DREs. Genes found HRPTECsexpression datawere used from publically available datasets via this approach were overlapped with the 4C-seq captured gene (NCBI Gene Expression Omnibus accession no. GSE12792).38 Ex- list to validate whether the 4C-seq approach indeed detected target pression data from microvascular endothelium were generated via genes that showed correlations in expression levels with the CKD- RNA extraction from cultured microvascular endothelial cells in low associated SNPs.

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Pathway Analyses Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Datasets were analyzed using QIAGEN IPA. IPAwas used to study both Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, enrichment of 4C-seq–identified genes in canonical pathways and Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, upstream regulators of identified candidate genes independently for P Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, HRGECs and HRPTECs. values were calculated on the basis of a Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, right-tailed Fisher exact test calculated by IPA. Expression levels of Krämer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller upstream regulators of which target genes were found enriched in the PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS: New loci candidate genes identified by 4C-seq were evaluated in a publically associated with kidney function and chronic kidney disease. Nat Genet 42: 376–384, 2010 available microarray dataset, which was used to study gene expression 3. Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F, Takahashi A, Maeda in CKD in renal biopsy specimens (NCBI Gene Expression Omnibus S, Tsunoda T, Chen P, Lim SC, Wong TY, Liu J, Young TL, Aung T, accession no. GSE66494).18 Seielstad M, Teo YY, Kim YJ, Lee JY, Han BG, Kang D, Chen CH, Tsai FJ, Chang LC, Fann SJ, Mei H, Rao DC, Hixson JE, Chen S, Katsuya T, Isono M, Ogihara T, Chambers JC, Zhang W, Kooner JS, Albrecht E, ACKNOWLEDGMENTS Yamamoto K, Kubo M, Nakamura Y, Kamatani N, Kato N, He J, Chen YT, Cho YS, Tai ES, Tanaka T; KidneyGen Consortium; CKDGen Con- fi We thank the Utrecht Sequencing Facility for providing the sequencing sortium; GUGC consortium: Meta-analysis identi es multiple loci as- sociated with kidney function-related traits in east Asian populations. service and data. The Utrecht Sequencing Facility is subsidized by the Nat Genet 44: 904–909, 2012 University Medical Center (UMC) Utrecht, the Hubrecht Institute, and 4. Raychaudhuri S, Plenge RM, Rossin EJ, Ng AC, Purcell SM, Sklar P, Utrecht University. Scolnick EM, Xavier RJ, Altshuler D, Daly MJ; International Schizo- This work was supported by The Netherlands Organisation for phrenia Consortium: Identifying relationships among genomic disease Scientific Research Vidi grants 016096359 (to M.C.V.) and 91714302 regions: Predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet 5: e1000534, 2009 (to C.C.), The Netherlands Foundation for Cardiovascular Excellence 5. Li G, Vega R, Nelms K, Gekakis N, Goodnow C, McNamara P, Wu H, (C.C.), the Erasmus Medical Center fellowship grant (to C.C.), the Hong NA, Glynne R: A role for Alström syndrome protein, alms1, in Regenerative Medicine fellowship grant of the UMC Utrecht (to C.C.), kidney ciliogenesis and cellular quiescence. PLoS Genet 3: e8, 2007 and The Netherlands Cardiovascular Research Initiative, which is 6. Mo L, Huang HY, Zhu XH, Shapiro E, Hasty DL, Wu XR: Tamm-Horsfall an initiative with support of the Alexandre Suerman Stipendium protein is a critical renal defense factor protecting against calcium ox- alate crystal formation. Kidney Int 66: 1159–1166, 2004 (the UMC Utrecht; to C.A.M.), the OZF/2012 Wilhelmina Child- 7. Ghirotto S, Tassi F, Barbujani G, Pattini L, Hayward C, Vollenweider P, ren’s Hospital fund (to C.A.M.), and Dutch Heart Foundation Bochud M, Rampoldi L, Devuyst O: The uromodulin gene locus shows grant CVON2014-11 RECONNECT (to D.J.D., M.C.V., J.A.J., evidence of pathogen adaptation through human evolution. JAmSoc M.M., and C.C.). Nephrol 27: 2983–2996, 2016 8. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, DISCLOSURES Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, None. 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476 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 462–476, 2018

Supplemental figure 1: The majority of genes identified with 4C-seq were positioned up to 500kbp from the CKD associated SNP locus. Graph shows the distance from the SNP to the TSS of the target genes found with 4C in HRGECs (X-axis), expressed as the number of target genes (frequency on Y- axis) per 100kbp. The majority of target genes was positioned up to 500kbp from the SNP, but occasionally candidate genes were found at locations over 1.5mb from the SNP locus (A). The TSS of the majority of candidate genes found with 4C in HRPTECs was positioned up to 500kbp from the SNP position, but some candidate genes were found at locations over 1.5mbp from the SNP locus (B).

Supplemental figure 2: Target genes of DREs colocalizing with CKD-associated SNPs, highlighted in red, are enriched in the mevalonate pathway and the trans, trans-farnesyl diphosphate biosynthesis pathway (adapted from IPA). Supplemental table 1: Primer design for cloning DREs from the rs11959928 region into the STARR-seq reporter plasmid.

SNP ID Chromosome Forward primer Reversed primer Location (GRCh37/hg19) chr5 ACATGGCCTATCCCTTTCCT GGATTTCCACCAGATGTTGC 39353419-39354619 chr5 CCAGTGTTAGTGCTGTTGTTGC CCCCATCCTCTGCCACTA 39355029-39356229 chr5 CAGGGTGGGTAGAGACGAGT ACCATCTCTGTGGCTCAGGT 39359279-39360479 chr5 TTGCTAACATTTGTGAGTGCTT TCCTACCTCTACAGGTTGTCACAT 39360189-39361389 chr5 ACCACATAAAGTCAAAGGAAGAA TGTGTCCTGCTGTGAGGAAT 39360529-39361729 chr5 TCAGGCTTTTCCTACCTTGC GCTATGTACTGGCAGCAGCTC 39368449-39369649 chr5 GGCATGCTGGCTGTTAAAGT CTGTTGCATGAGGTGAGTGG 39370239-39371439 rs11959928 chr5 GCACCTGGATAAGCCAGATAA GGCATAATTTTCTATCAGCTTCC 39370869-39372069 chr5 AGCCTGGGTGACAGAGTGAG TGGGAGGTGGAGGACTGTAG 39379474-39380674 chr5 GGGGCAACTACCAATAAGCA CCAATCGACACCTTCTTCGT 39382029-39383229 chr5 GCGTATTTTCTTCCTTGCTTG GCCTGACCCTGCTTAGCTT 39396569-39397769 chr5 AAAATCAATCCGCCATAAGC GGTGCAGCTGTCGCTATGTA 39400609-39401809 chr5 GGCAAAGCTGGGTGTAAGTT GCCCTCTCCACTGTGTCAG 39405129-39406329 chr5 GCTGAACGCTATAGCCCTGT CAGCCTCCTCTCCTGTCAAA 39411679-39412879 chr5 TTTGGGAATCCAGGACTGAG TTCTTGGCACTGGTCTTTCC 39412649-39413849 Supplemental table 2: Comparison of reference allele prevalence (Δ) for each variant in rs11959928 locus in STARR-seq library (input) with reference allele prevalence in transcribed RNA of HRGECs, HRPTECs, and HEK293a after transformation with STARR-seq library. Regions in bold are described in figure 2C.

SNP ID Chromosome Location input 1 Input 2 HRGECs 1 HRGECs 2 Δ HRGECs 1 Δ HRGECs 2 chr5 39353722 70.5 54.5 57.4 44.1 -13.1 -10.4 chr5 39354039 97.5 89.7 94.1 98.2 -3.4 8.5 chr5 39355135 19.2 18.4 15.3 15.6 -3.9 -2.8 chr5 39355591 83.4 88.4 84.8 82.4 1.5 -6.0 chr5 39355648 82.0 87.1 83.8 83.6 1.8 -3.6 chr5 39356000 86.3 86.3 83.0 82.5 -3.2 -3.8 chr5 39359597 88.8 84.8 82.0 76.0 -6.8 -8.9 chr5 39359698 77.5 98.9 71.0 76.8 -6.4 -22.0 chr5 39360817 94.1 89.1 94.6 87.4 0.5 -1.7 chr5 39361231 72.8 69.1 100.0 100.0 27.2 30.9 chr5 39361273 74.8 71.2 100.0 100.0 25.2 28.8 chr5 39361303 36.5 31.8 17.8 3.2 -18.7 -28.6 chr5 39361359 70.2 64.8 100.0 99.1 29.8 34.3 chr5 39361382 91.2 91.5 91.4 91.1 0.2 -0.5 chr5 39361387 89.6 90.7 88.9 90.0 -0.7 -0.7 chr5 39361556 89.4 94.0 81.1 80.0 -8.3 -14.0 chr5 39361573 48.9 45.2 100.0 99.6 51.1 54.3 chr5 39368773 95.3 69.7 92.9 96.7 -2.4 27.0 chr5 39368977 82.6 95.5 88.2 86.4 5.5 -9.1 chr5 39369030 78.6 96.1 84.8 84.4 6.3 -11.7 rs11959928 chr5 39369103 87.2 95.5 79.4 83.9 -7.7 -11.5 chr5 39369492 94.9 90.7 95.7 92.8 0.8 2.1 chr5 39370386 98.7 94.3 94.9 96.9 -3.7 2.6 chr5 39370397 83.7 75.8 78.6 74.3 -5.1 -1.5 chr5 39370442 99.2 97.6 95.0 98.0 -4.1 0.4 chr5 39371493 44.5 45.2 44.1 41.6 -0.4 -3.7 chr5 39382261 58.8 56.3 57.0 55.9 -1.8 -0.4 chr5 39397132 74.0 71.8 73.3 71.8 -0.7 0.0 chr5 39397662 80.5 78.1 84.8 82.2 4.2 4.1 chr5 39400701 81.1 87.1 87.5 81.7 6.3 -5.4 chr5 39401049 82.7 70.4 80.9 77.7 -1.8 7.3 chr5 39401384 79.9 83.3 84.0 81.1 4.1 -2.2 chr5 39401620 64.1 52.3 60.0 62.6 -4.1 10.3 chr5 39405736 58.7 62.2 59.6 59.3 0.9 -2.8 chr5 39406098 66.4 66.8 64.3 65.1 -2.1 -1.7 chr5 39412248 74.4 83.6 77.7 71.5 3.3 -12.1 chr5 39412480 97.5 100.0 95.3 96.4 -2.2 -3.6 chr5 39412568 23.8 15.6 9.9 13.6 -13.9 -2.0 chr5 39412681 9.9 8.9 7.5 7.2 -2.4 -1.7 chr5 39412798 15.4 10.0 14.0 19.8 -1.4 9.8 SNP ID Chromosome Location input 1 Input 2 HRPTECs 1 HRPTECs 2 Δ HRPTECs 1 Δ HRPTECs 2 chr5 39353722 70.5 54.5 65.2 54.7 -5.3 0.1 chr5 39354039 97.5 89.7 83.1 88.0 -14.4 -1.7 chr5 39355135 19.2 18.4 14.8 16.6 -4.4 -1.8 chr5 39355591 83.4 88.4 82.6 83.9 -0.8 -4.4 chr5 39355648 82.0 87.1 81.6 81.3 -0.4 -5.8 chr5 39356000 86.3 86.3 82.8 82.4 -3.4 -3.9 chr5 39359597 88.8 84.8 74.1 68.9 -14.7 -15.9 chr5 39359698 77.5 98.9 71.3 80.5 -6.2 -18.4 chr5 39360817 94.1 89.1 100.0 75.8 5.9 -13.3

rs11959928 chr5 39361231 72.8 69.1 100.0 100.0 27.2 30.9 chr5 39361273 74.8 71.2 100.0 100.0 25.2 28.8 chr5 39361303 36.5 31.8 8.3 23.2 -28.1 -8.6 chr5 39361359 70.2 64.8 100.0 100.0 29.8 35.2 chr5 39361382 91.2 91.5 100.0 79.4 8.8 -12.2 chr5 39361387 89.6 90.7 100.0 76.2 10.4 -14.5 chr5 39361556 89.4 94.0 96.0 91.1 6.6 -2.9 chr5 39361573 48.9 45.2 100.0 100.0 51.1 54.8 chr5 39368773 95.3 69.7 80.1 100.0 -15.2 30.3 chr5 39368977 82.6 95.5 59.6 83.9 -23.1 -11.5 chr5 39369030 78.6 96.1 64.8 69.8 -13.8 -26.3 rs11959928 chr5 39369103 87.2 95.5 99.0 63.5 11.8 -32.0 chr5 39369492 94.9 90.7 100.0 73.3 5.1 -17.4 chr5 39370386 98.7 94.3 84.0 83.0 -14.7 -11.3 chr5 39370397 83.7 75.8 63.5 86.0 -20.1 10.2 chr5 39370442 99.2 97.6 84.2 75.9 -14.9 -21.6 chr5 39371493 44.5 45.2 44.7 42.4 0.2 -2.8 chr5 39382261 58.8 56.3 51.3 55.5 -7.5 -0.9 chr5 39397132 74.0 71.8 82.7 72.1 8.7 0.3 chr5 39397662 80.5 78.1 81.5 84.3 1.0 6.2 chr5 39400701 81.1 87.1 73.9 84.4 -7.3 -2.8 chr5 39401049 82.7 70.4 88.2 84.4 5.6 14.0 chr5 39401384 79.9 83.3 90.5 77.7 10.7 -5.6 chr5 39401620 64.1 52.3 60.4 52.8 -3.7 0.5 chr5 39405736 58.7 62.2 57.3 61.7 -1.4 -0.5 chr5 39406098 66.4 66.8 62.9 67.5 -3.5 0.7 chr5 39412248 74.4 83.6 70.3 90.4 -4.1 6.8 chr5 39412480 97.5 100.0 71.8 99.4 -25.7 -0.6 chr5 39412568 23.8 15.6 21.9 9.4 -1.9 -6.2 chr5 39412681 9.9 8.9 18.1 1.3 8.2 -7.6 chr5 39412798 15.4 10.0 22.7 3.5 7.3 -6.5 SNP ID Chromosome Location input 1 Input 2 HEK293a 1 HEK293a 2 Δ HEK293a 1 Δ HEK293a 2 chr5 39353722 70.5 54.5 62.8 58.9 -7.7 4.3 chr5 39354039 97.5 89.7 93.1 95.9 -4.4 6.2 chr5 39355135 19.2 18.4 16.3 15.9 -2.9 -2.5 chr5 39355591 83.4 88.4 83.5 83.3 0.1 -5.1 chr5 39355648 82.0 87.1 83.2 83.3 1.1 -3.8 chr5 39356000 86.3 86.3 82.9 82.0 -3.4 -4.3 chr5 39359597 88.8 84.8 79.3 92.3 -9.5 7.5 chr5 39359698 77.5 98.9 76.6 79.1 -0.9 -19.7 chr5 39360817 94.1 89.1 100.0 90.7 5.9 1.5 chr5 39361231 72.8 69.1 100.0 100.0 27.2 30.9 chr5 39361273 74.8 71.2 100.0 100.0 25.2 28.8 chr5 39361303 36.5 31.8 9.1 19.8 -27.4 -12.1 chr5 39361359 70.2 64.8 100.0 100.0 29.8 35.2 chr5 39361382 91.2 91.5 76.1 83.3 -15.1 -8.2 chr5 39361387 89.6 90.7 71.2 82.2 -18.4 -8.5 chr5 39361556 89.4 94.0 81.4 59.8 -8.0 -34.2 chr5 39361573 48.9 45.2 98.9 100.0 49.9 54.8 chr5 39368773 95.3 69.7 90.6 90.4 -4.8 20.7 chr5 39368977 82.6 95.5 77.7 88.4 -4.9 -7.0 chr5 39369030 78.6 96.1 78.6 90.5 0.0 -5.5 rs11959928 chr5 39369103 87.2 95.5 82.5 86.2 -4.7 -9.3 chr5 39369492 94.9 90.7 94.8 97.8 -0.1 7.1 chr5 39370386 98.7 94.3 98.9 85.8 0.2 -8.4 rs11959928

chr5 39370397 83.7 75.8 74.7 85.7 -8.9 10.0 chr5 39370442 99.2 97.6 99.1 93.6 -0.1 -3.9 chr5 39371493 44.5 45.2 42.0 45.5 -2.4 0.3 chr5 39382261 58.8 56.3 58.1 56.5 -0.7 0.2 chr5 39397132 74.0 71.8 73.6 77.1 -0.4 5.3 chr5 39397662 80.5 78.1 80.6 81.5 0.1 3.4 chr5 39400701 81.1 87.1 71.2 83.0 -9.9 -4.1 chr5 39401049 82.7 70.4 83.3 81.8 0.6 11.4 chr5 39401384 79.9 83.3 81.2 80.7 1.4 -2.7 chr5 39401620 64.1 52.3 68.1 68.0 4.0 15.7 chr5 39405736 58.7 62.2 57.3 58.1 -1.4 -4.1 chr5 39406098 66.4 66.8 64.2 62.8 -2.2 -4.0 chr5 39412248 74.4 83.6 79.7 80.7 5.3 -2.9 chr5 39412480 97.5 100.0 97.8 94.9 0.3 -5.1 chr5 39412568 23.8 15.6 6.3 8.8 -17.5 -6.7 chr5 39412681 9.9 8.9 0.9 4.6 -9.1 -4.3 chr5 39412798 15.4 10.0 10.3 9.7 -5.1 -0.3 Supplemental table 3: Datasets used for selection of active DNA regulatory elements.

Cell type Dataset Library strategie GSM1014519_hg19_wgEncodeUwDgfHmvechPk.narrowPeak Dnase hypersensitivity GSM1014529_hg19_wgEncodeUwDgfHmvecbPk.narrowPeak Dnase hypersensitivity GSM1014532_hg19_wgEncodeUwDgfHmvecdPk.narrowPeak Dnase hypersensitivity GSM1024745_hg19_wgEncodeUwDnaseHmvecdadPkRep1.narrowPeak Dnase hypersensitivity GSM1024747_hg19_wgEncodeUwDnaseHmvecdadPkRep2.narrowPeak Dnase hypersensitivity GSM646570_hg19_wgEncodeUwDgfHmvecdbladPkV2.narrowPeak Dnase hypersensitivity GSM736521_hg19_wgEncodeUwDnaseHmvecdblneoPkRep2.narrowPeak Dnase hypersensitivity HRGECs GSM736523_hg19_wgEncodeUwDnaseHmvecdbladPkRep2.narrowPeak Dnase hypersensitivity GSM736571_hg19_wgEncodeUwDnaseHmvecdblneoPkRep1.narrowPeak Dnase hypersensitivity GSM736573_hg19_wgEncodeUwDnaseHmvecdlyneoPkRep2.narrowPeak Dnase hypersensitivity GSM736577_hg19_wgEncodeUwDnaseHmvecdlyneoPkRep1.narrowPeak Dnase hypersensitivity GSM736591_hg19_wgEncodeUwDnaseHmvecdlyadPkRep2.narrowPeak Dnase hypersensitivity GSM736599_hg19_wgEncodeUwDnaseHmvecdlyadPkRep1.narrowPeak Dnase hypersensitivity GSM736609_hg19_wgEncodeUwDnaseHmvecdbladPkRep1.narrowPeak Dnase hypersensitivity GSM736539_hg19_wgEncodeUwDnaseRptecPkRep2.narrowPeak Dnase hypersensitivity GSM736543_hg19_wgEncodeUwDnaseRptecPkRep1.narrowPeak Dnase hypersensitivity GSM736549_hg19_wgEncodeUwDnaseHrcePkRep1.narrowPeak Dnase hypersensitivity GSM736557_hg19_wgEncodeUwDnaseHrcePkRep2.narrowPeak Dnase hypersensitivity GSM849027_hg19_wgEncodeUwDgfHrcePk.narrowPeak Dnase hypersensitivity GSM945216_hg19_wgEncodeUwHistoneRptecH3k04me3StdPkRep1.narrowPeak H3K04me3 ChIP-seq GSM945216_hg19_wgEncodeUwHistoneRptecH3k04me3StdPkRep2.narrowPeak H3K04me3 ChIP-seq Fetal_Kidney.H-22337.DS10986 Dnase hypersensitivity HRPTECs Fetal_Kidney.H-22676.DS12635 Dnase hypersensitivity Fetal_Kidney.H-23524.DS16139 Dnase hypersensitivity Fetal_Kidney.H-23663.DS16837 Dnase hypersensitivity Fetal_Kidney.H-23855.DS17522 Dnase hypersensitivity Fetal_Kidney.H-23914.DS17753 Dnase hypersensitivity Fetal_Kidney.H-24507.DS20564 Dnase hypersensitivity Fetal_Kidney.H-24510.DNase.DS20786 Dnase hypersensitivity Fetal_Kidney.H-24584.DS20987 Dnase hypersensitivity Fetal_Kidney.H-24608.DNase.DS21096 Dnase hypersensitivity Supplemental table 4: CKD candidate genes retrieved by 4C-seq in HRGECs. * only trait serum creatinine, ** only trait serum urate, *** only trait blood urea nitrogen,nsnon-synonymous SNP. Interacting genes with a P-value <1E-08 in both individual 4C-seq experiments in HRGECs are expressed in bold.

SNP Gene ID Refseq Chromosome P-value prep 1 P-value prep 2 expression (RPKM) SNP-TSS (kbp) PMVK NM_006556 1 8,58E-03 1,23E-11 3,45 285 PBXIP1 NM_020524 1 1,00E+00 1,32E-13 5,39 266 PYGO2 NM_138300 1 8,58E-03 1,32E-13 3,07 261 SHC1 NM_001130040 1 8,58E-03 1,32E-13 6,88 252 CKS1B NM_001826 1 8,58E-03 1,32E-13 3,78 248 FLAD1 NM_025207 1 8,58E-03 1,32E-13 3,20 239 LENEP NM_018655 1 3,82E-04 1,32E-13 -3,32 229 ZBTB7B NM_015872 1 3,82E-04 1,23E-11 3,23 220 DCST2 NM_144622 1 3,82E-04 1,01E-17 -1,63 189 DCST1 NM_001143687 1 3,82E-04 1,01E-17 -0,93 189 ADAM15 NM_207191 1 3,82E-04 1,01E-17 7,92 171 EFNA4 NM_005227 1 3,82E-04 1,01E-17 3,90 159 EFNA3 NM_004952 1 3,36E-07 2,78E-24 0,54 144 EFNA1 NM_004428 1 1,52E-30 6,97E-29 5,03 95 RAG1AP1 NM_001122839 1 3,36E-37 6,97E-29 3,33 87 DPM3 NM_018973 1 1,80E-39 1,20E-33 4,14 82 KRTCAP2 NM_173852 1 4,44E-84 1,69E-62 5,60 49 TRIM46 NM_025058 1 4,44E-84 1,69E-62 1,77 49 MUC1 NM_001018016 1 4,44E-84 4,54E-77 -0,18 32 MIR92B NR_030281 1 4,44E-84 4,21E-80 -3,32 30 rs2049805 THBS3 NM_007112 1 4,44E-84 1,12E-92 2,05 17 MTX1 NM_002455 1 4,44E-84 1,12E-92 2,14 16 GBAP NR_002188 1 4,44E-84 1,12E-92 2,81 2 GBA NM_000157 1 4,44E-84 1,12E-92 4,84 16 FAM189B NM_006589 1 4,44E-84 1,12E-92 4,32 30 SCAMP3 NM_005698 1 4,44E-84 1,12E-92 4,91 37 CLK2 NM_003993 1 4,44E-84 3,26E-68 3,63 48 HCN3 NM_020897 1 1,27E-73 3,18E-46 0,35 52 PKLR NM_181871 1 3,36E-37 1,46E-26 -1,33 76 FDPS NM_002004 1 3,72E-24 1,46E-26 6,54 84 RUSC1 NM_001105203 1 4,30E-22 1,46E-26 3,07 96 C1orf104 NM_001039517 1 4,30E-22 1,46E-26 4,36 99 MIR555 NR_030282 1 1,36E-10 1,24E-15 -0,41 121 LOC645676 NR_027023 1 7,33E-09 4,77E-22 -0,98 337 ASH1L NM_018489 1 7,33E-09 4,77E-22 1,65 337 MSTO1 NM_018116 1 7,33E-09 7,36E-20 1,93 385 YY1AP1 NM_139119 1 7,33E-09 1,01E-17 3,71 464 DAP3 NM_004632 1 7,33E-09 1,01E-17 4,11 464 MSTO2P NR_024117 1 1,27E-05 9,75E-10 2,27 521 SSR2 NM_003145 1 2,26E-04 9,75E-10 6,98 796 ANP32E NM_001136479 1 1,37E-11 3,12E-15 3,22 744 CA14 NM_012113 1 3,04E-13 5,71E-23 -1,64 721 APH1A NM_001077628 1 3,04E-13 6,13E-21 5,58 710 C1orf54 NM_024579 1 5,37E-10 1,46E-08 2,94 706 C1orf51 NM_144697 1 1,37E-11 3,12E-15 -0,01 696 MRPS21 NM_018997 1 3,04E-13 4,53E-17 4,81 685 PRPF3 NM_004698 1 3,04E-13 1,84E-13 3,45 658 RPRD2 NM_015203 1 1,00E-16 1,82E-29 2,59 614 TARS2 NM_025150 1 2,34E-26 3,13E-27 2,06 492 ECM1 NM_004425 1 3,04E-13 5,71E-23 2,45 471 ADAMTSL4 NM_025008 1 5,88E-15 6,13E-21 0,15 430 MCL1 NM_182763 1 1,00E-16 5,67E-19 5,63 399 ENSA NM_207045 1 1,96E-28 1,82E-29 5,50 350 GOLPH3L NM_018178 1 5,79E-35 3,13E-27 3,34 282 HORMAD1 NM_032132 1 5,79E-35 4,57E-25 -3,32 258 CTSS NM_004079 1 1,00E-16 1,82E-29 2,40 213 CTSK NM_000396 1 1,96E-28 8,92E-32 0,83 171 ARNT NM_001668 1 5,73E-42 3,20E-39 2,78 102 SETDB1 NM_001145415 1 1,41E-39 3,63E-34 2,40 53 rs267734 LASS2 NM_022075 1 1,14E-60 3,94E-51 5,41 4 ANXA9 NM_003568 1 1,14E-60 3,94E-51 0,42 3 rs267734

FAM63A NM_001163260 1 9,96E-58 3,94E-51 2,58 28 PRUNE NM_021222 1 9,96E-58 3,94E-51 1,16 29 BNIPL NM_138278 1 1,41E-39 6,48E-42 -1,96 58 C1orf56 NM_017860 1 5,79E-35 3,20E-39 2,15 69 CDC42SE1 NM_001038707 1 1,47E-30 1,21E-36 4,38 81 MLLT11 NM_006818 1 1,47E-30 1,21E-36 4,74 81 GABPB2 NM_144618 1 2,34E-26 1,21E-36 0,36 92 SEMA6C NM_030913 1 1,41E-39 3,63E-34 4,01 168 TNFAIP8L2 NM_024575 1 1,41E-39 3,63E-34 -2,03 178 LYSMD1 NM_212551 1 1,41E-39 3,63E-34 0,54 187 SCNM1 NM_024041 1 1,41E-39 3,63E-34 4,13 187 TMOD4 NM_013353 1 1,96E-28 8,92E-32 -1,24 197 VPS72 NM_005997 1 1,96E-28 8,92E-32 4,68 211 PIP5K1A NM_001135636 1 1,96E-28 8,92E-32 3,54 220 PSMD4 NM_002810 1 5,37E-10 6,13E-21 5,60 276 RFX5 NM_000449 1 5,08E-07 9,33E-12 3,20 368 SNX27 NM_030918 1 2,26E-04 9,33E-12 1,90 633 PRPF40A NM_017892 2 2,16E-05 8,71E-13 3,18 39595 ARL6IP6 NM_152522 2 2,16E-05 8,71E-13 2,51 39595 RPRM NM_019845 2 6,56E-14 1,36E-14 -3,32 40356 rs11123170*** GALNT13 NM_052917 2 8,68E-18 2,17E-20 -3,32 40749 KCNJ3 NM_002239 2 2,16E-05 8,71E-13 -2,92 41576 CYTIP NM_004288 2 2,16E-05 2,24E-09 -3,32 44322 CGREF1 NM_001166241 2 1,00E+00 7,61E-09 -0,50 397 ABHD1 NM_032604 2 1,00E+00 7,61E-09 -0,16 384 PREB NM_013388 2 1,00E+00 7,61E-09 3,97 373 C2orf53 NM_178553 2 1,00E+00 7,61E-09 -3,32 369 TCF23 NM_175769 2 1,88E-03 7,61E-09 -3,32 359 MPV17 NM_002437 2 6,30E-09 4,24E-05 4,88 185 GTF3C2 NM_001035521 2 6,30E-09 3,91E-15 3,23 151 EIF2B4 NM_172195 2 5,84E-11 5,07E-22 3,60 138 SNX17 NM_014748 2 5,84E-11 5,07E-22 4,87 138 ZNF513 NM_144631 2 5,84E-11 5,07E-22 2,58 127 FTHL3P NR_002201 2 4,51E-13 2,27E-17 3,01 114 rs1260326ns PPM1G NM_002707 2 1,68E-17 2,15E-29 5,71 98 NRBP1 NM_013392 2 1,40E-24 2,15E-29 5,56 79 KRTCAP3 NM_173853 2 3,41E-51 3,39E-37 0,29 66 IFT172 NM_015662 2 4,71E-96 1,09E-89 1,71 18 FNDC4 NM_022823 2 9,85E-100 3,14E-97 2,99 13 GCKR NM_001486 2 9,85E-100 3,14E-97 -1,35 11 C2orf16 NM_032266 2 3,41E-51 1,26E-42 -0,78 68 ZNF512 NM_032434 2 4,92E-40 1,26E-42 3,01 75 GPN1 NM_001145047 2 4,92E-40 6,88E-40 3,94 121 CCDC121 NM_001142682 2 4,92E-40 6,88E-40 -0,29 121 SLC4A1AP NM_018158 2 1,50E-29 1,14E-19 3,13 155 SUPT7L NM_014860 2 1,50E-29 1,14E-19 2,71 156 FBXO41 NM_001080410 2 2,47E-13 1,29E-12 -1,23 370 EGR4 NM_001965 2 2,14E-17 1,29E-12 -2,53 348 ALMS1 NM_015120 2 1,65E-19 1,52E-16 0,02 255 NAT8 NM_003960 2 2,74E-83 3,15E-62 -2,47 1 ALMS1P NR_003683 2 2,74E-83 3,15E-62 -2,64 4 NAT8B NM_016347 2 9,52E-46 1,42E-39 -1,78 60 TPRKB NM_016058 2 1,27E-35 7,85E-45 2,49 96 DUSP11 NM_003584 2 9,30E-54 4,98E-37 2,78 139 C2orf78 NM_001080474 2 9,30E-54 4,98E-37 -3,32 143 STAMBP NM_201647 2 9,30E-54 4,21E-32 2,42 188 ACTG2 NM_001615 2 1,13E-21 1,34E-18 -2,56 252 DGUOK NM_080916 2 1,65E-19 1,03E-20 3,49 286 TET3 NM_144993 2 1,65E-19 6,94E-23 1,51 405 rs13538ns BOLA3 NM_001035505 2 8,42E-31 1,03E-20 3,41 507 MOBKL1B NM_018221 2 1,88E-28 1,52E-16 4,61 538 MTHFD2 NM_006636 2 2,14E-17 2,93E-07 2,93 557 SLC4A5 NM_133478 2 1,65E-19 1,51E-14 -1,27 702 DCTN1 NM_001135041 2 2,14E-11 5,77E-09 5,36 734 LOC100189589 NR_024463 2 2,14E-11 1,51E-14 -2,44 745 INO80B NM_031288 2 2,14E-11 3,78E-04 3,13 814 rs13538ns

WBP1 NM_012477 2 2,14E-11 3,78E-04 4,37 817 MOGS NM_001146158 2 2,14E-11 3,78E-04 4,81 824 MRPL53 NM_053050 2 2,14E-11 3,78E-04 4,78 832 TTC31 NM_022492 2 2,14E-11 5,77E-09 2,54 842 CCDC142 NM_032779 2 2,14E-11 5,77E-09 1,11 842 LOC151534 NR_024606 2 1,92E-04 9,40E-11 1,90 861 C3orf50 NR_021485 3 3,46E-07 3,88E-09 -2,78 623 MECOM NM_001163999 3 1,82E-34 9,92E-17 3,24 287 TERC NR_001566 3 1,76E-18 8,29E-13 -1,83 332 ARPM1 NM_032487 3 1,76E-18 3,88E-09 0,42 337 rs16853722 MYNN NM_018657 3 1,76E-18 3,88E-09 1,35 340 LRRC34 NM_153353 3 1,99E-16 2,97E-04 -1,89 380 LRRIQ4 NM_001080460 3 7,01E-09 2,97E-04 -3,32 389 LOC100128164 NR_027622 3 7,01E-09 7,36E-03 -2,94 534 SEC62 NM_003262 3 7,01E-09 7,36E-03 3,49 534 SLC25A26 NM_173471 3 1,00E+00 2,48E-09 0,95 680 LRIG1 NM_015541 3 5,48E-24 2,43E-20 1,40 248 rs13069000*** KBTBD8 NM_032505 3 7,52E-07 2,48E-09 -0,93 250 FAM19A4 NM_001005527 3 8,18E-14 2,48E-09 -2,22 2183 BCL6 NM_001134738 3 1,06E-19 7,61E-29 1,59 261 FLJ42393 NR_024413 3 9,48E-22 2,31E-33 -2,74 183 rs10937329*** LPP NM_005578 3 9,37E-16 1,88E-22 2,28 217 TPRG1 NM_198485 3 1,50E-08 1,87E-09 -2,97 1176 ZBTB38 NM_001080412 3 3,89E-15 1,63E-07 3,36 764 RASA2 NM_006506 3 2,92E-13 4,50E-09 0,81 601 RNF7 NM_183237 3 2,92E-13 3,25E-14 4,46 350 GRK7 NM_139209 3 2,92E-13 4,53E-16 -2,33 310 ATP1B3 NM_001679 3 4,44E-17 5,53E-20 6,59 212 TFDP2 NM_006286 3 3,33E-40 5,72E-31 2,04 83 rs347685 GK5 NM_001039547 3 1,68E-25 2,16E-33 -0,06 137 XRN1 NM_001042604 3 3,67E-21 2,16E-33 1,29 360 ATR NM_001184 3 4,44E-17 3,25E-14 1,08 491 PLS1 NM_001145319 3 4,49E-08 3,25E-14 -2,87 508 TRPC1 NM_003304 3 4,49E-08 1,99E-12 -0,17 636 PCOLCE2 NM_013363 3 4,49E-08 4,50E-09 -3,32 801 PAQR9 NM_198504 3 1,87E-11 4,50E-09 -3,32 875 SDAD1 NM_018115 4 7,94E-08 4,93E-11 2,63 500 CXCL9 NM_002416 4 5,87E-07 4,93E-11 -3,32 484 ART3 NM_001130017 4 5,87E-07 4,93E-11 -2,62 480 CXCL10 NM_001565 4 5,87E-07 8,82E-13 -1,00 467 CXCL11 NM_005409 4 1,34E-08 8,82E-13 1,13 455 NUP54 NM_017426 4 6,62E-16 1,96E-20 2,65 342 SCARB2 NM_005506 4 4,07E-12 1,35E-14 5,54 277 rs13146355 FAM47E NM_001136570 4 6,24E-20 7,82E-27 -3,32 239 STBD1 NM_003943 4 5,01E-22 7,88E-39 0,33 184 CCDC158 NM_001042784 4 2,00E-67 1,40E-65 -3,32 84 SHROOM3 NM_020859 4 7,32E-98 6,43E-85 0,05 56 ANKRD56 NM_001029870 4 5,01E-22 1,67E-22 -3,32 407 40067 NM_018243 4 6,62E-16 1,23E-24 4,68 459 CCNI NM_006835 4 6,62E-16 1,96E-20 6,32 585 CCNG2 NM_004354 4 5,58E-14 1,23E-24 2,29 666 SPARCL1 NM_001128310 4 9,04E-10 4,53E-13 0,12 509 DSPP NM_014208 4 9,04E-10 6,40E-03 -3,32 430 IBSP NM_004967 4 1,42E-04 2,49E-09 -3,32 239 MEPE NM_020203 4 1,15E-15 1,42E-07 -3,32 206 SPP1 NM_000582 4 5,15E-36 1,26E-32 -2,59 63 PKD2 NM_000297 4 1,27E-67 3,37E-61 2,24 31 rs2725220** ABCG2 NM_004827 4 1,36E-33 1,26E-32 0,51 120 PPM1K NM_152542 4 1,15E-15 3,82E-19 -0,05 246 HERC6 NM_001165136 4 1,15E-15 4,88E-15 0,79 340 HERC5 NM_016323 4 7,30E-29 4,60E-17 -0,55 418 PIGY NM_001042616 4 7,01E-20 4,60E-17 4,95 485 HERC3 NM_014606 4 6,04E-08 3,64E-11 1,30 554 NAP1L5 NM_153757 4 3,30E-06 3,64E-11 1,20 659 ART3 NM_001130017 4 5,87E-07 4,93E-11 -2,62 437

rs17319721 CXCL10 NM_001565 4 5,87E-07 8,82E-13 -1,00 424 CXCL11 NM_005409 4 1,34E-08 8,82E-13 1,13 412 NUP54 NM_017426 4 6,62E-16 1,96E-20 2,65 299 SCARB2 NM_005506 4 4,07E-12 1,35E-14 5,54 234 FAM47E NM_001136570 4 6,24E-20 7,82E-27 -3,32 196 rs17319721 STBD1 NM_003943 4 5,01E-22 7,88E-39 0,33 141 CCDC158 NM_001042784 4 2,00E-67 1,40E-65 -3,32 40 SHROOM3 NM_020859 4 7,32E-98 6,43E-85 0,05 13 ANKRD56 NM_001029870 4 5,01E-22 1,67E-22 -3,32 450 40067 NM_018243 4 6,62E-16 1,23E-24 4,68 502 CCNI NM_006835 4 6,62E-16 1,96E-20 6,32 628 OSMR NM_003999 5 1,14E-05 1,81E-13 2,36 551 RICTOR NM_152756 5 9,80E-11 2,55E-21 1,43 323 FYB NM_001465 5 1,43E-12 2,81E-17 -3,32 177 C9 NM_001737 5 3,50E-56 3,71E-50 -2,52 32 DAB2 NM_001343 5 2,61E-97 3,65E-65 6,21 28 rs11959928 PTGER4 NM_000958 5 2,84E-07 1,17E-11 3,01 1283 TTC33 NM_012382 5 1,43E-12 2,02E-23 0,51 1359 PRKAA1 NM_006251 5 8,32E-03 1,17E-11 3,38 1401 SNORD72 NR_002583 5 8,32E-03 6,44E-10 -3,32 1436 RPL37 NM_000997 5 8,32E-03 6,44E-10 6,48 1438 CARD6 NM_032587 5 8,32E-03 6,44E-10 3,47 1444 UIMC1 NM_016290 5 6,47E-06 4,81E-13 3,05 384 ZNF346 NM_012279 5 2,29E-03 4,81E-13 2,03 368 FGFR4 NM_002011 5 1,06E-13 2,79E-11 -1,10 304 NSD1 NM_172349 5 4,54E-19 1,03E-18 2,47 258 RAB24 NM_001031677 5 4,54E-19 2,69E-29 3,54 87 PRELID1 NM_013237 5 5,92E-21 2,69E-29 6,23 87 MXD3 NM_001142935 5 6,96E-23 2,69E-29 4,34 78 LMAN2 NM_006816 5 9,83E-57 6,19E-55 6,33 39 RGS14 NM_006480 5 2,09E-67 6,19E-55 1,73 33 SLC34A1 NM_003052 5 4,42E-73 5,97E-58 -3,32 6 rs6420094 PFN3 NM_001029886 5 5,74E-62 3,19E-49 -3,32 10 F12 NM_000505 5 9,83E-57 3,19E-49 -0,19 19 GRK6 NM_001004105 5 8,23E-47 1,69E-46 2,43 36 PRR7 NM_030567 5 8,23E-47 1,69E-46 2,49 56 DBN1 NM_080881 5 1,95E-44 7,51E-44 7,06 82 PDLIM7 NM_005451 5 3,13E-17 1,41E-31 6,14 107 DOK3 NM_001144875 5 3,13E-17 2,63E-36 1,22 120 DDX41 NM_016222 5 3,13E-17 2,63E-36 3,92 126 FAM193B NM_019057 5 7,94E-09 4,81E-13 2,87 164 TMED9 NM_017510 5 2,29E-03 2,79E-11 6,77 202 B4GALT7 NM_007255 5 1,00E+00 2,79E-11 3,72 209 HDDC2 NM_016063 6 1,25E-03 4,39E-12 0,81 1813 NCOA7 NM_001122842 6 1,63E-09 1,50E-04 3,29 1324 HINT3 NM_138571 6 1,63E-09 8,14E-14 1,93 1158 TRMT11 NM_001031712 6 1,28E-33 5,68E-37 0,23 1128 C6orf173 NM_001012507 6 1,28E-33 1,64E-25 3,59 775 rs1936800*** RSPO3 NM_032784 6 3,18E-60 1,17E-53 -2,18 4 RNF146 NM_030963 6 5,56E-36 1,13E-27 3,38 152 ECHDC1 NM_001139510 6 6,01E-13 7,92E-09 2,92 227 KIAA0408 NM_014702 6 1,63E-09 2,03E-10 -2,60 344 C6orf174 NM_001012279 6 6,61E-08 8,14E-14 -2,62 404 IPCEF1 NM_001130699 6 2,21E-24 8,12E-26 -2,31 335 CNKSR3 NM_173515 6 2,87E-40 7,98E-45 2,99 155 RBM16 NM_014892 6 6,84E-38 8,92E-40 2,95 68 rs9397738* TIAM2 NM_012454 6 1,38E-05 7,82E-09 0,18 425 CLDN20 NM_001001346 6 2,93E-14 1,69E-17 -2,05 598 TFB1M NM_016020 6 3,63E-18 1,69E-17 1,92 649 TJAP1 NM_001146016 6 4,43E-06 3,85E-09 3,10 361 C6orf154 NM_001012974 6 1,78E-04 3,85E-09 -1,98 328 YIPF3 NM_015388 6 1,78E-04 5,94E-11 6,02 322 POLR1C NM_203290 6 1,78E-04 5,94E-11 2,75 322 XPO5 NM_020750 6 1,22E-19 8,70E-35 2,72 263 POLH NM_006502 6 1,22E-19 8,70E-35 2,20 263 GTPBP2 NM_019096 6 1,21E-28 9,12E-40 4,01 210

rs881858 MAD2L1BP NM_001003690 6 1,21E-28 9,12E-40 3,27 209 RSPH9 NM_152732 6 7,32E-36 5,38E-30 -0,35 194 MRPS18A NM_018135 6 4,59E-46 6,17E-45 3,97 151 VEGFA NM_001025369 6 7,32E-36 9,12E-40 1,55 69 rs881858 LOC100132354 NR_024478 6 1,88E-43 2,97E-37 -3,32 52 C6orf223 NM_153246 6 5,25E-31 2,14E-25 -1,86 162 MRPL14 NM_032111 6 1,94E-15 7,23E-19 4,77 289 TMEM63B NM_018426 6 1,94E-15 7,23E-19 4,38 289 CAPN11 NM_007058 6 1,94E-15 7,76E-13 1,44 320 SLC29A1 NM_001078174 6 1,78E-04 3,85E-09 6,31 381 HSP90AB1 NM_007355 6 1,78E-04 5,94E-11 8,50 408 SLC35B2 NM_178148 6 4,43E-06 5,94E-11 4,77 419 NFKBIE NM_004556 6 4,43E-06 5,94E-11 3,12 427 TMEM151B NM_001137560 6 4,43E-06 5,94E-11 -2,45 432 SPATS1 NM_145026 6 4,43E-06 7,76E-13 -3,32 504 CDC5L NM_001253 6 1,78E-04 3,85E-09 3,31 549 PION NM_017439 7 4,03E-06 6,98E-11 -0,65 371 PTPN12 NM_002835 7 5,82E-22 6,98E-11 4,63 250 RSBN1L NM_198467 7 9,53E-44 2,41E-40 1,57 91 rs6465825* TMEM60 NM_032936 7 1,26E-91 4,93E-61 2,43 11 PHTF2 NM_001127360 7 1,26E-91 4,93E-61 0,40 12 CD36 NM_001001547 7 1,00E+00 1,17E-09 -2,44 2815 NUB1 NM_016118 7 3,43E-19 1,59E-30 3,38 369 WDR86 NM_198285 7 4,19E-15 3,46E-17 -3,32 301 CRYGN NM_144727 7 4,02E-17 3,82E-15 -3,32 271 rs7805747 RHEB NM_005614 7 4,07E-47 7,08E-43 4,31 191 PRKAG2 NM_024429 7 1,73E-57 5,49E-62 4,53 78 GALNTL5 NM_145292 7 2,12E-09 6,06E-06 -3,32 246 GALNT11 NM_022087 7 2,12E-09 1,27E-07 3,42 315 LOXL2 NM_002318 8 1,00E+00 7,16E-09 7,76 489 ENTPD4 NM_004901 8 6,08E-10 1,11E-17 3,46 436 SLC25A37 NM_016612 8 1,11E-06 6,10E-14 2,98 365 NKX3-1 NM_006167 8 2,86E-08 8,90E-16 -0,77 211 NKX2-6 NM_001136271 8 2,86E-08 8,90E-16 -3,32 187 rs10109414* STC1 NM_003155 8 4,79E-45 4,51E-44 1,93 39 ADAM28 NM_021777 8 2,18E-15 1,26E-30 -3,32 400 ADAMDEC1 NM_014479 8 2,47E-19 1,06E-21 -3,32 491 ADAM7 NM_003817 8 6,08E-10 6,10E-14 -3,32 547 NEFM NM_005382 8 1,00E+00 6,10E-14 -2,28 1020 PGM5 NM_021965 9 4,38E-12 1,55E-18 -2,67 463 LOC572558 NR_015423 9 4,38E-12 1,55E-18 -3,32 462 C9orf71 NM_153237 9 4,97E-24 1,55E-18 -3,32 279 rs4744712 PIP5K1B NM_003558 9 8,16E-18 1,55E-18 -3,32 114 FAM122A NM_138333 9 2,69E-64 4,19E-57 1,92 40 PRKACG NM_002732 9 2,68E-10 8,36E-27 -3,32 194 FXN NM_181425 9 2,68E-10 1,60E-20 0,58 216 LARP4B NM_015155 10 1,52E-08 2,41E-18 3,17 224 GTPBP4 NM_012341 10 1,41E-21 1,86E-16 3,50 122 C10orf110 NR_024628 10 1,01E-25 1,17E-39 1,18 88 IDI2 NM_033261 10 5,10E-30 1,17E-39 0,92 84 rs10794720 IDI1 NM_004508 10 1,10E-63 7,25E-52 4,69 61 WDR37 NM_014023 10 4,11E-77 1,95E-54 2,50 53 NCRNA00200 NR_015376 10 1,82E-53 1,79E-28 -3,32 50 PFKP NM_002627 10 3,09E-10 7,65E-13 6,54 1954 PITRM1 NM_014889 10 5,41E-12 2,30E-06 4,88 2059 CCDC88B NM_032251 11 5,53E-11 9,95E-11 -1,42 356 RPS6KA4 NM_001006944 11 5,53E-11 9,95E-11 3,80 337 SLC22A11 NM_018484 11 9,08E-15 2,09E-29 -3,32 141 SLC22A12 NM_144585 11 9,08E-15 4,24E-34 -3,32 106 NRXN2 NM_138734 11 8,66E-59 1,79E-41 -2,52 53 RASGRP2 NM_001098671 11 1,86E-69 3,32E-63 -2,74 48 PYGM NM_001164716 11 8,46E-32 2,97E-49 -2,28 64 SF1 NM_201995 11 9,07E-19 5,70E-39 5,60 82 MAP4K2 NM_004579 11 3,47E-09 1,71E-18 3,08 107 rs504915** CDC42BPG NM_017525 11 7,97E-06 5,95E-09 -1,66 148 EHD1 NM_006795 11 7,97E-06 9,95E-11 5,46 182 rs504915**

GPHA2 NM_130769 11 6,91E-03 1,83E-16 -3,32 239 C11orf85 NM_001037225 11 7,97E-06 1,83E-16 -3,32 264 BATF2 NM_138456 11 7,97E-06 9,95E-11 -1,31 300 ARL2 NM_001667 11 2,73E-04 9,95E-11 5,63 318 SNX15 NM_013306 11 2,73E-04 5,95E-09 3,05 331 CDCA5 NM_080668 11 2,73E-04 9,95E-11 2,55 388 ZFPL1 NM_006782 11 2,73E-04 9,95E-11 4,22 388 C11orf2 NM_013265 11 6,91E-03 9,95E-11 5,07 400 LOC100288778 NR_028269 12 4,34E-34 1,34E-20 2,31 261 FAM138D NR_026823 12 1,74E-41 6,37E-27 -3,32 200 IQSEC3 NM_015232 12 4,82E-44 4,57E-41 -2,34 163 SLC6A12 NM_001122847 12 5,26E-52 1,09E-57 -3,32 26 rs10774021* SLC6A13 NM_016615 12 2,33E-66 8,70E-52 -3,32 23 CCDC77 NM_001130147 12 7,16E-25 3,87E-29 1,32 149 KDM5A NM_001042603 12 7,16E-25 3,87E-29 1,97 149 B4GALNT3 NM_173593 12 6,25E-09 5,82E-13 -3,32 220 PPP1CC NM_002710 12 5,14E-03 5,01E-09 4,93 827 FAM109A NM_144671 12 1,37E-17 7,30E-21 3,00 201 SH2B3 NM_005475 12 9,92E-20 9,87E-19 5,40 164 ATXN2 NM_002973 12 4,32E-69 2,44E-66 3,25 30 BRAP NM_006768 12 2,12E-34 1,03E-41 2,01 116 rs653178 ACAD10 NM_001136542 12 2,12E-34 1,03E-41 1,00 116 ALDH2 NM_000690 12 7,49E-76 9,73E-89 4,48 197 MAPKAPK5 NM_003668 12 7,49E-76 9,73E-89 2,56 273 C12orf47 NR_015404 12 4,16E-73 9,73E-89 2,05 273 TMEM116 NM_138341 12 2,46E-08 4,42E-16 -0,15 443 ERP29 NM_001034025 12 2,46E-08 4,42E-16 5,23 443 DACH1 NM_004392 13 1,77E-35 2,32E-44 1,61 94 rs626277 C13orf37 NM_001071775 13 3,66E-07 5,13E-14 2,09 954 C13orf34 NM_024808 13 3,66E-07 5,13E-14 0,40 954 C15orf43 NM_152448 15 7,53E-05 3,56E-11 -3,32 392 DUOXA1 NM_144565 15 3,07E-06 3,77E-16 -2,74 219 DUOX1 NM_017434 15 3,07E-06 3,77E-16 -2,32 219 SHF NM_138356 15 6,33E-18 1,78E-25 -0,60 148 SLC28A2 NM_004212 15 4,92E-50 1,53E-40 -3,32 97 GATM NM_001482 15 1,25E-75 4,49E-64 -2,78 30 rs2453533* SPATA5L1 NM_024063 15 5,36E-43 8,53E-34 1,78 53 C15orf48 NM_032413 15 8,35E-20 9,82E-20 -1,75 82 MIR147B NR_030599 15 4,32E-16 3,77E-16 -0,12 84 C15orf21 NR_022014 15 6,88E-11 8,91E-13 0,04 162 SLC30A4 NM_013309 15 1,44E-12 8,91E-13 0,67 174 PLDN NM_012388 15 3,07E-06 3,77E-16 3,06 238 KIAA1370 NM_019600 15 5,41E-03 1,08E-09 2,64 937 ONECUT1 NM_004498 15 6,76E-09 5,86E-16 -2,75 826 rs17730281 WDR72 NM_182758 15 1,60E-18 4,19E-29 -3,32 144 RSL24D1 NM_016304 15 1,94E-09 2,68E-08 3,91 1581 ONECUT1 NM_004498 15 6,76E-09 5,86E-16 -2,75 861 rs17730436* WDR72 NM_182758 15 1,60E-18 4,19E-29 -3,32 109 UNC13C NM_001080534 15 7,21E-12 2,20E-12 -3,32 362 BCAS3 NM_001099432 17 7,93E-22 3,53E-21 1,99 484 TBX2 NM_005994 17 1,45E-75 3,41E-66 -2,70 238 rs11868441*** C17orf82 NM_203425 17 2,68E-40 2,26E-35 -1,95 250 NACA2 NM_199290 17 1,24E-27 1,53E-32 -0,87 429 BRIP1 NM_032043 17 3,45E-07 1,69E-12 0,23 702 PDCD5 NM_004708 19 1,65E-13 4,24E-19 4,84 285 ANKRD27 NM_032139 19 1,65E-13 1,32E-12 2,44 191 RGS9BP NM_207391 19 1,65E-13 1,32E-12 -2,39 191 NUDT19 NM_001105570 19 1,51E-18 1,72E-24 2,37 174 TDRD12 NM_001110822 19 2,84E-36 1,87E-34 -2,65 146 rs12460876 SLC7A9 NM_001126335 19 2,18E-50 3,07E-48 -2,32 4 CCDC123 NM_032816 19 1,51E-18 1,72E-24 2,35 106 C19orf40 NM_152266 19 1,51E-18 1,72E-24 0,73 106 RHPN2 NM_033103 19 3,88E-15 1,32E-12 -1,00 199 GPATCH1 NM_018025 19 3,88E-15 4,09E-11 0,47 215 WDR88 NM_173479 19 1,65E-13 4,09E-11 -2,29 266 RAE1 NM_003610 20 1,00E+00 3,40E-13 3,03 1543 PPP4R1L NR_003505 20 7,57E-09 1,66E-19 1,00 585 RAB22A NM_020673 20 7,57E-09 1,66E-19 2,16 584 VAPB NM_004738 20 3,30E-23 1,01E-24 3,13 505 APCDD1L NM_153360 20 7,57E-09 1,73E-06 -0,43 379 STX16 NM_001001433 20 3,08E-13 1,51E-26 3,62 243 NPEPL1 NM_024663 20 7,57E-09 3,37E-21 3,87 201 MIR296 NR_029844 20 7,71E-03 9,67E-12 -3,32 76 MIR298 NR_030580 20 7,71E-03 9,67E-12 -3,32 76 GNAS NM_016592 20 2,11E-16 1,06E-14 7,60 54 rs6026584 GNASAS NR_002785 20 1,93E-34 2,66E-32 -3,32 43 TH1L NM_198976 20 1,59E-55 1,24E-40 3,92 87 CTSZ NM_001336 20 4,40E-51 2,69E-52 7,11 113 TUBB1 NM_030773 20 4,42E-60 4,12E-63 -1,93 125 ATP5E NM_006886 20 4,42E-60 4,12E-63 7,09 138 SLMO2 NM_016045 20 4,42E-60 1,76E-57 3,47 149 ZNF831 NM_178457 20 7,57E-09 1,04E-07 -2,96 297 SYCP2 NM_014258 20 3,30E-06 5,39E-09 -2,57 1038 PPP1R3D NM_006242 20 3,30E-06 5,39E-09 0,96 1046 C20orf177 NM_022106 20 3,30E-06 5,39E-09 0,41 1046 SSTR4 NM_001052 20 1,40E-07 1,03E-10 -2,52 597 THBD NM_000361 20 2,79E-06 1,03E-10 2,89 582 NXT1 NM_013248 20 6,19E-29 3,44E-25 3,00 281 GZF1 NM_022482 20 7,76E-31 5,28E-27 0,94 268 NAPB NM_022080 20 9,06E-33 3,44E-25 0,61 211 CSTL1 NM_138283 20 9,06E-33 2,06E-23 -3,32 192 CST11 NM_080830 20 7,76E-31 1,12E-21 -3,32 179 CST8 NM_005492 20 7,57E-12 5,57E-20 -1,84 141 CSTT NR_001279 20 7,57E-12 2,52E-18 -3,32 113 rs911119 CST9L NM_080610 20 6,19E-29 9,54E-31 -3,32 63 CST9 NM_001008693 20 1,74E-77 4,12E-54 -3,32 26 CST3 NM_000099 20 4,95E-80 6,00E-64 7,87 6 CST4 NM_001899 20 1,00E-36 9,10E-41 -2,20 57 CST1 NM_001898 20 6,42E-20 2,06E-23 0,23 119 CST2 NM_001322 20 2,25E-13 1,03E-10 -2,16 195 CST5 NM_001900 20 2,25E-13 5,05E-08 -3,32 248 GGTLC1 NM_178312 20 6,49E-04 3,86E-12 -3,32 355 C20orf3 NM_020531 20 2,79E-06 2,44E-09 5,49 1361 Supplemental table 5: CKD candidate genes retrieved by 4C-seq in HRPTECs. * only trait serum creatinine, ** only trait serum urate, *** only trait blood urea nitrogen,nsnon-synonymous SNP. Interacting genes with a P-value <1E-08 in both individual 4C-seq experiments in HRPTECs are expressed in bold.

SNP Gene ID Refseq Chromosome P-value prep 1 P-value prep 2 expression (intensity) SNP-TSS (kbp) ADAR NM_001111 1 1,40E-15 6,02E-10 10,88 614 PMVK NM_006556 1 1,11E-09 1,97E-17 8,92 285 PBXIP1 NM_020524 1 1,11E-09 5,52E-26 9,31 266 PYGO2 NM_138300 1 1,40E-11 5,52E-26 8,86 261 SHC1 NM_001130040 1 1,40E-11 5,52E-26 11,07 252 CKS1B NM_001826 1 1,40E-11 5,52E-26 9,62 248 FLAD1 NM_025207 1 1,40E-15 1,97E-17 8,14 239 LENEP NM_018655 1 1,40E-15 1,79E-19 7,23 229 ZBTB7B NM_015872 1 1,40E-15 1,79E-19 8,21 220 DCST2 NM_144622 1 1,11E-09 1,97E-17 0,00 189 DCST1 NM_001143687 1 1,11E-09 1,97E-17 0,00 189 ADAM15 NM_207191 1 1,51E-13 4,31E-33 8,70 171 EFNA4 NM_005227 1 1,51E-13 4,31E-33 6,84 159 EFNA3 NM_004952 1 1,44E-26 1,16E-43 7,96 144 EFNA1 NM_004428 1 1,51E-46 1,32E-35 10,92 95 RAG1AP1 NM_001122839 1 1,51E-46 1,32E-35 9,08 87 DPM3 NM_018973 1 1,51E-46 1,32E-35 9,72 82 KRTCAP2 NM_173852 1 9,52E-55 6,99E-41 0,00 49 TRIM46 NM_025058 1 9,52E-55 6,99E-41 6,82 49 MUC1 NM_001018016 1 2,05E-72 1,33E-49 9,75 32 MIR92B NR_030281 1 1,50E-75 7,76E-53 0,00 30 THBS3 NM_007112 1 8,30E-89 2,17E-56 8,22 17 MTX1 NM_002455 1 8,30E-89 2,17E-56 9,91 16 GBAP NR_002188 1 8,30E-89 2,17E-56 6,46 2 GBA NM_000157 1 8,30E-89 2,17E-56 9,43 16 rs2049805 FAM189B NM_006589 1 8,30E-89 7,76E-53 9,99 30 SCAMP3 NM_005698 1 9,52E-79 7,76E-53 9,62 37 CLK2 NM_003993 1 1,43E-57 1,33E-49 9,18 48 HCN3 NM_020897 1 6,70E-44 1,33E-49 0,00 52 PKLR NM_181871 1 6,49E-29 1,46E-46 6,54 76 FDPS NM_002004 1 6,49E-29 1,46E-46 11,13 84 RUSC1 NM_001105203 1 6,49E-29 1,46E-46 9,11 96 C1orf104 NM_001039517 1 6,49E-29 1,46E-46 0,00 99 MIR555 NR_030282 1 1,40E-11 1,18E-30 0,00 121 LOC645676 NR_027023 1 1,40E-15 2,76E-28 0,00 337 ASH1L NM_018489 1 1,40E-15 2,76E-28 7,51 337 MSTO1 NM_018116 1 8,05E-20 1,40E-21 7,96 385 YY1AP1 NM_139119 1 1,51E-13 9,49E-24 8,47 464 DAP3 NM_004632 1 1,51E-13 9,49E-24 10,01 464 MSTO2P NR_024117 1 3,90E-06 9,49E-24 7,96 521 GON4L NM_001037533 1 7,30E-08 1,51E-13 4,81 632 SYT11 NM_152280 1 7,30E-08 1,51E-13 5,48 634 SNORA42 NR_002974 1 3,90E-06 6,02E-10 0,00 695 SCARNA4 NR_003005 1 3,90E-06 6,02E-10 0,00 701 KIAA0907 NM_014949 1 3,90E-06 6,02E-10 8,96 709 RXFP4 NM_181885 1 1,62E-04 6,02E-10 0,00 716 ARHGEF2 NM_004723 1 7,30E-08 6,02E-10 8,32 753 SSR2 NM_003145 1 3,90E-06 1,51E-13 10,69 796 UBQLN4 NM_020131 1 1,62E-04 1,51E-13 0,00 829 LMNA NM_005572 1 4,95E-03 1,04E-11 10,91 889 PDE4DIP NM_014644 1 1,01E-05 2,45E-11 6,59 5956 NOTCH2NL NM_203458 1 3,40E-10 5,46E-05 9,34 5742 NBPF10 NM_001039703 1 7,54E-12 2,45E-11 9,82 5658 HIST2H2BF NM_001024599 1 3,40E-10 4,19E-06 0,00 1552 HIST2H3D NM_001123375 1 3,40E-10 4,19E-06 0,00 1166 HIST2H4B NM_001034077 1 3,40E-10 4,19E-06 4,96 1147 HIST2H4A NM_003548 1 3,40E-10 4,19E-06 4,96 1147 HIST2H3C NM_021059 1 3,40E-10 2,66E-07 0,00 1139 HIST2H3A NM_001005464 1 3,40E-10 2,66E-07 0,00 1139 HIST2H2AA4 NM_001040874 1 3,40E-10 2,66E-07 10,93 1137 HIST2H2AA3 NM_003516 1 3,40E-10 2,66E-07 10,93 1137 OTUD7B NM_020205 1 7,54E-12 5,46E-05 5,56 969 PLEKHO1 NM_016274 1 2,05E-04 2,45E-11 6,61 829 ANP32E NM_001136479 1 1,41E-13 1,42E-08 7,80 744

rs267734 CA14 NM_012113 1 2,03E-25 2,22E-14 7,12 721 APH1A NM_001077628 1 3,52E-19 2,45E-11 9,57 710 C1orf54 NM_024579 1 7,54E-12 2,45E-11 7,93 706 C1orf51 NM_144697 1 7,54E-12 2,22E-14 0,00 696 MRPS21 NM_018997 1 3,40E-10 2,22E-14 0,00 685 PRPF3 NM_004698 1 1,41E-13 2,45E-11 7,38 658 RPRD2 NM_015203 1 5,84E-30 1,06E-17 8,70 614 TARS2 NM_025150 1 3,46E-21 2,55E-21 8,46 492 ECM1 NM_004425 1 3,52E-19 2,55E-21 8,07 471 ADAMTSL4 NM_025008 1 3,05E-17 2,85E-25 7,60 430 MCL1 NM_182763 1 3,05E-17 2,55E-21 9,87 399 ENSA NM_207045 1 2,31E-32 2,15E-27 10,77 350 GOLPH3L NM_018178 1 5,84E-30 5,09E-32 8,75 282 HORMAD1 NM_032132 1 2,03E-25 2,99E-23 0,00 258 CTSS NM_004079 1 2,03E-25 1,79E-19 7,09 213 CTSK NM_000396 1 7,23E-35 5,09E-32 8,13 171 ARNT NM_001668 1 2,95E-40 1,24E-29 5,78 102 rs267734 SETDB1 NM_001145415 1 7,23E-35 1,34E-34 8,06 53 LASS2 NM_022075 1 1,67E-46 1,68E-37 11,33 4 ANXA9 NM_003568 1 1,67E-46 1,68E-37 6,59 3 FAM63A NM_001163260 1 1,67E-46 1,68E-37 10,09 28 PRUNE NM_021222 1 1,67E-46 1,34E-34 9,13 29 BNIPL NM_138278 1 2,95E-40 1,34E-34 0,00 58 C1orf56 NM_017860 1 2,95E-40 1,34E-34 6,22 69 CDC42SE1 NM_001038707 1 1,72E-37 1,34E-34 9,44 81 MLLT11 NM_006818 1 1,72E-37 1,34E-34 10,52 81 GABPB2 NM_144618 1 7,23E-35 1,34E-34 0,00 92 SEMA6C NM_030913 1 1,72E-37 5,09E-32 8,25 168 TNFAIP8L2 NM_024575 1 1,72E-37 5,09E-32 0,00 178 LYSMD1 NM_212551 1 1,72E-37 5,09E-32 0,00 187 SCNM1 NM_024041 1 1,72E-37 5,09E-32 9,51 187 TMOD4 NM_013353 1 5,84E-30 1,24E-29 0,00 197 VPS72 NM_005997 1 7,23E-35 1,24E-29 9,59 211 PIP5K1A NM_001135636 1 7,23E-35 2,99E-23 9,54 220 PSMD4 NM_002810 1 3,52E-19 2,45E-11 10,16 276 ZNF687 NM_020832 1 3,40E-10 2,45E-11 0,00 303 PI4KB NM_002651 1 3,40E-10 1,42E-08 8,92 347 RFX5 NM_000449 1 3,40E-10 1,42E-08 8,32 368 SELENBP1 NM_003944 1 3,40E-10 5,46E-05 8,23 394 PSMB4 NM_002796 1 3,40E-10 2,45E-11 11,07 421 POGZ NM_015100 1 3,40E-10 5,46E-05 9,36 480 TUFT1 NM_001126337 1 1,41E-13 4,19E-06 8,84 561 MIR554 NR_030280 1 1,41E-13 4,19E-06 0,00 567 MUC1 NM_001018016 1 2,05E-72 1,33E-49 9,75 4211 MIR92B NR_030281 1 1,50E-75 7,76E-53 0,00 4213 THBS3 NM_007112 1 8,30E-89 2,17E-56 8,22 4226 GBAP NR_002188 1 8,30E-89 2,17E-56 6,46 4246 GBA NM_000157 1 8,30E-89 2,17E-56 9,43 4260 GPR113 NM_001145169 2 1,00E+00 5,56E-08 0,00 1189 SELI NM_033505 2 1,00E+00 1,26E-09 0,00 1162 DPYSL5 NM_020134 2 4,39E-08 3,64E-13 0,00 660 MAPRE3 NM_012326 2 6,39E-12 5,56E-08 5,90 537 TMEM214 NM_001083590 2 1,00E+00 2,34E-11 9,15 475 AGBL5 NM_001035507 2 5,84E-10 4,75E-15 8,39 456 LOC100128731 NM_001134693 2 5,84E-10 2,34E-11 0,00 436 EMILIN1 NM_007046 2 5,84E-10 5,65E-05 6,32 430 CGREF1 NM_001166241 2 1,23E-04 1,26E-09 5,70 397 ABHD1 NM_032604 2 2,65E-06 4,75E-15 0,00 384 PREB NM_013388 2 4,39E-08 4,75E-15 9,12 373 C2orf53 NM_178553 2 4,39E-08 4,75E-15 0,00 369 TCF23 NM_175769 2 4,39E-08 4,75E-15 0,00 359 C2orf28 NM_080592 2 4,39E-08 4,75E-15 10,69 296 SLC5A6 NM_021095 2 4,39E-08 4,75E-15 8,65 296 CAD NM_004341 2 4,17E-03 3,64E-13 9,34 291 SLC30A3 NM_003459 2 5,87E-14 5,23E-17 8,48 245 DNAJC5G NM_173650 2 6,39E-12 1,26E-09 0,00 233 TRIM54 NM_032546 2 6,39E-12 5,23E-17 0,00 225 UCN NM_003353 2 6,39E-12 3,86E-21 6,73 200 MPV17 NM_002437 2 5,84E-10 6,73E-28 9,51 185 rs1260326ns GTF3C2 NM_001035521 2 5,87E-14 4,88E-19 9,51 151 rs1260326ns EIF2B4 NM_172195 2 5,87E-14 1,44E-25 9,58 138 SNX17 NM_014748 2 4,59E-16 1,44E-25 9,85 138 ZNF513 NM_144631 2 9,05E-23 8,05E-33 0,00 127 FTHL3P NR_002201 2 9,05E-23 8,05E-33 0,00 114 PPM1G NM_002707 2 9,05E-23 6,73E-28 8,82 98 NRBP1 NM_013392 2 5,30E-30 1,70E-47 9,09 79 KRTCAP3 NM_173853 2 3,43E-43 1,70E-47 0,00 66 IFT172 NM_015662 2 5,44E-68 1,70E-47 0,00 18 FNDC4 NM_022823 2 5,44E-68 1,70E-47 8,14 13 GCKR NM_001486 2 1,20E-71 1,70E-47 6,01 11 C2orf16 NM_032266 2 3,35E-61 1,70E-47 0,00 68 ZNF512 NM_032434 2 7,61E-52 4,93E-41 0,00 75 GPN1 NM_001145047 2 1,59E-64 1,70E-47 10,00 121 CCDC121 NM_001142682 2 1,59E-64 1,70E-47 4,35 121 SLC4A1AP NM_018158 2 9,67E-38 3,70E-38 8,09 155 SUPT7L NM_014860 2 9,67E-38 3,70E-38 7,05 156 MRPL33 NM_004891 2 1,23E-04 5,23E-17 10,85 264 RBKS NM_022128 2 6,39E-12 2,34E-11 9,45 382 BRE NM_199193 2 6,39E-12 2,34E-11 9,60 383 LOC100302650 NR_028308 2 6,39E-12 2,34E-11 0,00 383 FOSL2 NM_005253 2 1,23E-04 1,26E-09 8,24 885 PLB1 NM_153021 2 4,39E-08 1,26E-09 0,00 988 CYP26B1 NM_019885 2 1,00E+00 1,51E-10 5,27 1493 NOTO NM_001134462 2 4,60E-05 6,12E-09 0,00 439 SMYD5 NM_006062 2 4,60E-05 6,12E-09 8,46 427 C2orf7 NM_032319 2 3,10E-13 3,14E-12 0,00 408 CCT7 NM_001009570 2 3,10E-13 3,14E-12 11,13 407 FBXO41 NM_001080410 2 5,53E-19 5,95E-28 7,67 370 EGR4 NM_001965 2 4,13E-23 3,42E-30 4,40 348 ALMS1 NM_015120 2 1,83E-27 1,34E-21 7,91 255 NAT8 NM_003960 2 5,91E-56 1,42E-57 7,05 1 ALMS1P NR_003683 2 5,91E-56 1,42E-57 0,00 4 NAT8B NM_016347 2 2,37E-39 1,89E-42 7,05 60 rs13538ns TPRKB NM_016058 2 1,83E-27 1,69E-32 8,78 96 DUSP11 NM_003584 2 1,83E-27 3,42E-30 8,68 139 C2orf78 NM_001080474 2 1,83E-27 3,42E-30 0,00 143 STAMBP NM_201647 2 1,83E-27 1,17E-23 9,44 188 ACTG2 NM_001615 2 4,33E-15 1,51E-10 7,55 252 DGUOK NM_080916 2 4,60E-05 1,51E-10 9,76 286 TET3 NM_144993 2 5,25E-17 6,12E-09 8,55 405 BOLA3 NM_001035505 2 5,53E-19 8,61E-16 0,00 507 MOBKL1B NM_018221 2 4,60E-05 6,12E-09 7,73 538 SLC4A5 NM_133478 2 4,33E-15 3,14E-12 6,36 702 DCTN1 NM_001135041 2 1,58E-06 3,14E-12 8,55 734 LOC100189589 NR_024463 2 4,38E-08 3,14E-12 0,00 745 GOLIM4 NM_014498 3 3,40E-08 4,97E-10 7,13 1337 MIR551B NR_030294 3 1,13E-14 2,22E-18 0,00 881 C3orf50 NR_021485 3 6,03E-13 3,75E-13 0,00 623 MECOM NM_001163999 3 1,90E-26 2,69E-24 8,45 287 TERC NR_001566 3 2,52E-18 1,45E-16 0,00 332 rs16853722 ARPM1 NM_032487 3 1,13E-14 1,49E-11 0,00 337 MYNN NM_018657 3 1,13E-14 4,97E-10 7,80 340 LRRC34 NM_153353 3 6,03E-13 4,97E-10 0,00 380 LRRC31 NM_024727 3 3,40E-08 3,75E-13 5,22 437 SAMD7 NM_182610 3 1,05E-09 4,97E-10 0,00 479 GPR160 NM_014373 3 9,11E-07 4,97E-10 0,00 605 SLC25A26 NM_173471 3 1,00E+00 1,24E-08 0,00 680 LRIG1 NM_015541 3 1,76E-29 7,99E-29 7,05 248 rs13069000*** KBTBD8 NM_032505 3 1,08E-11 1,18E-16 0,00 250 FAM19A4 NM_001005527 3 1,08E-11 6,64E-15 0,00 2183 SST NM_001048 3 5,42E-05 3,26E-10 7,94 326 RTP2 NM_001004312 3 1,33E-09 1,45E-13 0,00 293 BCL6 NM_001134738 3 2,06E-29 4,75E-21 8,93 261 rs10937329*** FLJ42393 NR_024413 3 5,77E-39 2,54E-27 0,00 183 LPP NM_005578 3 1,04E-31 3,63E-25 9,73 217 TPRG1 NM_198485 3 1,33E-09 4,75E-21 0,00 1176 ACPL2 NM_001037172 3 4,28E-09 1,22E-09 0,00 856 RASA2 NM_006506 3 1,87E-12 2,29E-16 6,23 601

rs347685 RNF7 NM_183237 3 4,19E-16 4,02E-22 9,33 350 GRK7 NM_139209 3 4,96E-18 3,23E-18 0,00 310 ATP1B3 NM_001679 3 3,26E-24 3,90E-20 11,29 212 TFDP2 NM_006286 3 2,56E-41 5,72E-41 6,60 83 GK5 NM_001039547 3 1,88E-33 1,22E-35 0,00 137 rs347685 XRN1 NM_001042604 3 4,38E-22 3,90E-20 0,00 360 ATR NM_001184 3 4,19E-16 3,24E-11 6,30 491 PLS1 NM_001145319 3 1,87E-12 3,87E-08 9,65 508 TRPC1 NM_003304 3 1,56E-07 3,24E-11 8,71 636 PCOLCE2 NM_013363 3 1,56E-07 3,24E-11 5,68 801 PAQR9 NM_198504 3 4,63E-06 3,24E-11 0,00 875 SR140 NM_001080415 3 1,56E-07 1,22E-09 8,99 913 PPEF2 NM_006239 4 8,77E-10 1,49E-09 4,27 588 NAAA NM_001042402 4 4,50E-05 2,64E-16 6,83 550 SDAD1 NM_018115 4 1,58E-11 3,09E-24 9,11 500 CXCL9 NM_002416 4 1,58E-11 3,09E-24 6,81 484 ART3 NM_001130017 4 1,58E-11 4,05E-20 4,57 480 CXCL10 NM_001565 4 1,58E-11 3,55E-18 6,94 467 CXCL11 NM_005409 4 1,58E-11 3,55E-18 4,17 455 NUP54 NM_017426 4 1,04E-25 4,54E-31 8,48 342 SCARB2 NM_005506 4 2,22E-31 2,13E-33 10,39 277 rs13146355 FAM47E NM_001136570 4 7,94E-33 1,08E-28 0,00 239 STBD1 NM_003943 4 1,01E-38 2,13E-33 9,61 184 CCDC158 NM_001042784 4 5,67E-58 8,31E-47 0,00 84 SHROOM3 NM_020859 4 4,98E-71 2,33E-53 0,00 56 ANKRD56 NM_001029870 4 3,18E-19 1,08E-28 0,00 407 40067 NM_018243 4 1,04E-25 1,98E-26 10,05 459 CCNI NM_006835 4 9,43E-27 3,55E-18 12,59 585 CCNG2 NM_004354 4 2,55E-21 3,55E-18 9,63 666 CXCL13 NM_006419 4 5,02E-04 1,49E-09 4,75 1021 CNOT6L NM_144571 4 8,77E-10 4,67E-08 0,00 1328 USP17 NM_001105662 4 4,05E-11 2,41E-05 0,00 778 USP17L6P NR_027279 4 4,05E-11 2,41E-05 0,00 626 DEFB131 NM_001040448 4 4,05E-11 2,41E-05 0,00 549 rs3775948** DRD5 NM_000798 4 7,79E-35 1,13E-37 7,42 212 SLC2A9 NM_020041 4 9,56E-61 7,50E-62 10,09 28 WDR1 NM_005112 4 4,05E-11 1,05E-19 11,37 123 ZNF518B NM_053042 4 5,46E-17 8,07E-14 0,00 464 NAAA NM_001042402 4 4,50E-05 2,64E-16 6,83 507 SDAD1 NM_018115 4 1,58E-11 3,09E-24 9,11 457 CXCL9 NM_002416 4 1,58E-11 3,09E-24 6,81 440 ART3 NM_001130017 4 1,58E-11 4,05E-20 4,57 437 CXCL10 NM_001565 4 1,58E-11 3,55E-18 6,94 424 NUP54 NM_017426 4 1,04E-25 4,54E-31 8,48 299 SCARB2 NM_005506 4 2,22E-31 2,13E-33 10,39 234 rs17319721 FAM47E NM_001136570 4 7,94E-33 1,08E-28 0,00 196 STBD1 NM_003943 4 1,01E-38 2,13E-33 9,61 141 CCDC158 NM_001042784 4 5,67E-58 8,31E-47 0,00 40 SHROOM3 NM_020859 4 4,98E-71 2,33E-53 0,00 13 ANKRD56 NM_001029870 4 3,18E-19 1,08E-28 0,00 450 40067 NM_018243 4 1,04E-25 1,98E-26 10,05 502 CCNI NM_006835 4 9,43E-27 3,55E-18 12,59 628 CCNG2 NM_004354 4 2,55E-21 3,55E-18 9,63 710 EGFLAM NM_152403 5 1,53E-03 3,94E-09 0,00 1139 LIFR NM_001127671 5 3,07E-06 3,10E-12 4,58 840 OSMR NM_003999 5 9,74E-08 3,94E-09 9,98 551 RICTOR NM_152756 5 5,60E-31 3,01E-23 0,00 323 FYB NM_001465 5 2,32E-16 3,01E-23 7,11 177 C9 NM_001737 5 1,41E-48 3,18E-43 4,47 32 DAB2 NM_001343 5 1,93E-57 3,18E-43 10,81 28 PTGER4 NM_000958 5 2,55E-09 6,77E-14 4,42 1283 TTC33 NM_012382 5 2,32E-16 3,11E-21 6,49 1359 rs11959928 PRKAA1 NM_006251 5 1,04E-12 2,00E-17 6,56 1401 SNORD72 NR_002583 5 2,76E-22 1,26E-15 0,00 1436 RPL37 NM_000997 5 2,76E-22 1,26E-15 12,75 1438 CARD6 NM_032587 5 2,76E-22 1,26E-15 0,00 1444 C7 NM_000587 5 2,55E-09 1,26E-15 4,63 1512 C6 NM_000065 5 3,07E-06 3,94E-09 6,27 1817 C5orf51 NM_175921 5 5,58E-11 4,55E-05 0,00 2507 rs11959928

FBXO4 NM_033484 5 2,55E-09 2,46E-06 0,00 2528 C5orf39 NM_001014279 5 2,55E-09 7,56E-03 0,00 3643 LOC153684 NR_015447 5 2,55E-09 6,69E-04 0,00 3645 SNCB NM_001001502 5 9,33E-05 3,99E-10 7,40 760 EIF4E1B NM_001099408 5 9,33E-05 3,99E-10 0,00 760 TSPAN17 NM_001006616 5 3,51E-09 2,86E-13 0,00 743 UIMC1 NM_016290 5 3,87E-16 2,86E-13 8,41 384 ZNF346 NM_012279 5 1,58E-12 1,16E-11 0,00 368 FGFR4 NM_002011 5 2,66E-14 1,96E-20 7,13 304 NSD1 NM_172349 5 2,25E-28 1,56E-18 7,13 258 RAB24 NM_001031677 5 3,41E-26 1,22E-26 0,00 87 PRELID1 NM_013237 5 3,41E-26 1,22E-26 0,00 87 MXD3 NM_001142935 5 1,30E-30 1,59E-36 8,01 78 LMAN2 NM_006816 5 7,08E-51 8,35E-34 9,38 39 RGS14 NM_006480 5 4,59E-48 1,59E-36 7,83 33 rs6420094 SLC34A1 NM_003052 5 8,41E-54 1,44E-39 7,19 6 PFN3 NM_001029886 5 2,38E-45 1,44E-39 0,00 10 F12 NM_000505 5 2,38E-45 1,44E-39 8,83 19 GRK6 NM_001004105 5 3,65E-40 1,44E-39 7,32 36 PRR7 NM_030567 5 4,59E-48 1,44E-39 8,01 56 DBN1 NM_080881 5 4,59E-48 1,59E-36 9,38 82 PDLIM7 NM_005451 5 2,91E-35 8,35E-34 8,35 107 DOK3 NM_001144875 5 1,30E-30 1,59E-36 7,45 120 DDX41 NM_016222 5 1,30E-30 1,59E-36 11,05 126 FAM193B NM_019057 5 2,66E-14 1,22E-26 8,20 164 TMED9 NM_017510 5 8,08E-11 3,99E-10 10,49 202 B4GALT7 NM_007255 5 8,08E-11 3,99E-10 8,46 209 NHP2 NM_017838 5 8,08E-11 5,51E-06 11,09 763 HDDC2 NM_016063 6 9,64E-07 1,76E-17 5,74 1813 HEY2 NM_012259 6 2,85E-20 1,76E-17 5,62 1365 NCOA7 NM_001122842 6 2,88E-11 3,38E-23 0,00 1324 HINT3 NM_138571 6 1,17E-14 2,64E-19 0,00 1158 TRMT11 NM_001031712 6 1,06E-41 7,49E-35 8,01 1128 C6orf173 NM_001012507 6 8,90E-29 7,49E-35 0,00 775 rs1936800*** RSPO3 NM_032784 6 6,43E-45 7,49E-35 0,00 4 RNF146 NM_030963 6 2,28E-24 3,30E-32 8,05 152 ECHDC1 NM_001139510 6 2,49E-18 2,64E-19 9,46 227 KIAA0408 NM_014702 6 2,85E-20 3,38E-23 5,32 344 C6orf174 NM_001012279 6 2,88E-11 2,64E-19 0,00 404 C6orf58 NM_001010905 6 9,64E-07 2,64E-19 0,00 462 C6orf108 NM_006443 6 1,67E-05 1,29E-11 9,21 609 SLC22A7 NM_006672 6 4,38E-07 4,19E-15 6,67 541 CRIP3 NM_206922 6 1,67E-05 4,19E-15 0,00 530 ZNF318 NM_014345 6 1,59E-10 5,88E-17 7,06 469 ABCC10 NM_033450 6 9,23E-09 1,98E-08 8,25 407 DLK2 NM_023932 6 1,59E-10 5,53E-10 7,52 383 TJAP1 NM_001146016 6 1,59E-10 1,29E-11 8,43 361 C6orf154 NM_001012974 6 9,23E-09 2,53E-13 0,00 328 YIPF3 NM_015388 6 1,67E-05 2,53E-13 8,83 322 POLR1C NM_203290 6 1,67E-05 2,53E-13 8,62 322 XPO5 NM_020750 6 1,40E-22 5,89E-23 0,00 263 POLH NM_006502 6 1,40E-22 5,89E-23 4,78 263 GTPBP2 NM_019096 6 1,91E-29 1,12E-29 9,15 210 MAD2L1BP NM_001003690 6 1,91E-29 1,12E-29 8,81 209 RSPH9 NM_152732 6 7,41E-32 1,12E-29 0,00 194 rs881858 MRPS18A NM_018135 6 3,77E-42 2,97E-40 9,29 151 VEGFA NM_001025369 6 6,61E-45 2,97E-40 10,92 69 LOC100132354 NR_024478 6 1,79E-39 2,32E-37 0,00 52 C6orf223 NM_153246 6 2,50E-34 4,13E-32 0,00 162 MRPL14 NM_032111 6 2,07E-20 1,12E-29 0,00 289 TMEM63B NM_018426 6 2,07E-20 1,12E-29 0,00 289 CAPN11 NM_007058 6 2,07E-20 2,39E-27 6,01 320 SLC29A1 NM_001078174 6 9,23E-09 2,53E-13 9,23 381 HSP90AB1 NM_007355 6 2,30E-12 6,99E-21 10,74 408 SLC35B2 NM_178148 6 1,59E-10 6,99E-21 0,00 419 NFKBIE NM_004556 6 1,59E-10 6,99E-21 8,61 427 TMEM151B NM_001137560 6 1,59E-10 5,88E-17 6,94 432 TCTE1 NM_182539 6 4,38E-07 4,13E-25 0,00 459 AARS2 NM_020745 6 2,81E-14 6,98E-19 0,00 474 rs881858

SPATS1 NM_145026 6 9,23E-09 6,98E-19 0,00 504 CDC5L NM_001253 6 2,94E-16 1,29E-11 8,51 549 FNDC1 NM_032532 6 7,71E-05 4,27E-10 0,00 1078 SOD2 NM_001024465 6 2,57E-09 1,28E-16 12,08 554 WTAP NM_152858 6 1,51E-03 3,23E-13 10,78 520 ACAT2 NM_005891 6 9,75E-08 6,97E-15 10,02 485 SNORA20 NR_002960 6 9,75E-08 1,27E-11 11,22 467 SNORA29 NR_002965 6 3,06E-06 4,27E-10 0,00 462 TCP1 NM_001008897 6 3,06E-06 1,27E-11 11,22 458 MRPL18 NM_014161 6 3,06E-06 1,27E-11 10,30 457 PNLDC1 NM_173516 6 9,75E-08 6,97E-15 0,00 447 rs2279463* MAS1 NM_002377 6 3,06E-06 2,67E-20 6,52 340 IGF2R NM_000876 6 7,71E-05 3,23E-13 9,29 278 LOC729603 NR_003288 6 2,16E-26 2,19E-26 0,00 154 SLC22A1 NM_153187 6 9,40E-43 6,88E-31 7,25 126 SLC22A2 NM_003058 6 7,15E-66 1,03E-41 8,05 12 SLC22A3 NM_021977 6 3,03E-40 7,12E-36 4,17 101 LPAL2 NR_028093 6 2,85E-24 1,38E-28 5,71 264 AGPAT4 NM_020133 6 1,51E-03 4,27E-10 7,43 1027 LOC441177 NR_027284 6 7,71E-05 4,27E-10 0,00 5733 CYP2W1 NM_017781 7 9,56E-03 4,81E-11 5,93 262 MIR339 NR_029898 7 4,38E-04 8,50E-13 0,00 223 GPR146 NM_138445 7 2,71E-18 8,50E-13 0,00 188 GPER NM_001039966 7 2,29E-20 1,01E-24 5,40 159 C7orf50 NM_001134395 7 8,84E-39 4,14E-39 0,00 107 ZFAND2A NM_182491 7 2,66E-41 8,33E-42 0,00 85 UNCX NM_001080461 7 1,56E-66 1,42E-47 0,00 13 rs10277115 MICALL2 NM_182924 7 2,29E-20 1,42E-22 7,09 214 INTS1 NM_001080453 7 1,39E-10 3,20E-29 6,78 259 MAFK NM_002360 7 3,81E-07 1,64E-16 6,50 285 TMEM184A NM_001097620 7 1,39E-10 9,09E-08 0,00 311 PSMG3 NM_032302 7 1,39E-10 8,50E-13 0,00 324 KIAA1908 NR_021487 7 1,39E-10 8,50E-13 0,00 325 TFAMP1 NR_001288 7 1,47E-05 1,28E-14 0,00 369 ELFN1 NM_001128636 7 1,39E-10 4,81E-11 0,00 464 ZP3 NM_007155 7 1,00E+00 3,63E-09 6,73 1390 SRCRB4D NM_080744 7 1,00E+00 3,63E-09 0,00 1377 DTX2 NM_001102594 7 1,00E+00 3,63E-09 6,77 1325 FDPSL2A NR_003262 7 1,00E+00 3,63E-09 0,00 1312 UPK3B NM_182684 7 1,00E+00 3,63E-09 7,11 1277 POMZP3 NM_152992 7 2,68E-05 9,32E-16 7,09 1160 CCDC146 NM_020879 7 7,92E-07 3,63E-09 0,00 665 FGL2 NM_006682 7 7,92E-07 5,38E-14 5,02 587 rs6465825* PION NM_017439 7 5,72E-12 1,36E-17 7,93 371 PTPN12 NM_002835 7 5,29E-22 4,83E-28 8,92 250 RSBN1L NM_198467 7 1,43E-41 9,86E-36 0,00 91 TMEM60 NM_032936 7 3,04E-57 8,49E-39 0,00 11 PHTF2 NM_001127360 7 3,04E-57 8,49E-39 4,64 12 RPL13AP17 NR_003680 7 2,68E-05 1,36E-17 0,00 560 GNAI1 NM_002069 7 1,00E+00 1,06E-10 7,39 2348 FAM185A NM_001145268 7 1,86E-08 2,61E-12 0,00 24973 OR2A42 NM_001001802 7 1,00E+00 6,78E-09 0,00 7478 OR2A1 NM_001005287 7 1,00E+00 6,78E-09 0,00 7478 ATG9B NM_173681 7 1,00E+00 2,22E-10 0,00 686 ABCB8 NM_007188 7 1,00E+00 2,22E-10 7,92 682 ACCN3 NM_004769 7 1,00E+00 6,78E-09 5,82 662 CDK5 NM_004935 7 1,00E+00 6,78E-09 8,79 653 SLC4A2 NM_003040 7 1,00E+00 6,78E-09 9,58 651 FASTK NM_006712 7 6,14E-04 6,78E-09 9,05 630 TMUB1 NM_031434 7 6,14E-04 6,78E-09 0,00 627 AGAP3 NM_001042535 7 6,14E-04 2,22E-10 0,00 624 GBX1 NM_001098834 7 2,30E-05 6,15E-12 7,84 543 ASB10 NM_001142459 7 6,67E-07 6,78E-09 0,00 523 rs7805747 ABCF2 NM_005692 7 6,67E-07 2,22E-10 7,10 483 CHPF2 NM_019015 7 6,67E-07 6,15E-12 8,63 478 MIR671 NR_030407 7 1,56E-08 1,44E-13 8,63 472 SMARCD3 NM_001003801 7 1,56E-08 1,44E-13 7,66 462 NUB1 NM_016118 7 1,70E-28 5,75E-27 0,00 369 WDR86 NM_198285 7 8,75E-18 5,75E-27 0,00 301 rs7805747

CRYGN NM_144727 7 8,75E-18 1,55E-31 0,00 271 RHEB NM_005614 7 4,60E-43 1,71E-42 8,09 191 PRKAG2 NM_024429 7 6,52E-54 1,38E-36 8,34 78 GALNTL5 NM_145292 7 6,67E-07 2,89E-15 0,00 246 GALNT11 NM_022087 7 1,56E-08 2,22E-10 10,53 315 ACTR3B NM_001040135 7 1,00E+00 2,22E-10 6,23 1049 TNFRSF10D NM_003840 8 1,39E-05 2,43E-09 7,48 730 LOXL2 NM_002318 8 1,39E-05 8,58E-11 9,07 489 ENTPD4 NM_004901 8 1,28E-11 1,33E-15 7,01 436 SLC25A37 NM_016612 8 6,89E-19 3,39E-19 8,42 365 NKX3-1 NM_006167 8 2,51E-13 2,33E-17 7,43 211 NKX2-6 NM_001136271 8 6,90E-21 4,05E-21 0,00 187 rs10109414* STC1 NM_003155 8 2,91E-40 1,81E-32 10,31 39 ADAM28 NM_021777 8 5,81E-23 3,90E-23 4,73 400 ADAMDEC1 NM_014479 8 1,10E-29 1,70E-27 4,32 491 ADAM7 NM_003817 8 4,15E-15 2,95E-25 6,93 547 KCTD9 NM_017634 8 2,63E-04 8,58E-11 7,99 1565 CDCA2 NM_152562 8 2,63E-04 8,58E-11 0,00 1565 LARP4B NM_015155 10 5,66E-11 6,27E-10 6,66 224 GTPBP4 NM_012341 10 3,04E-16 3,69E-16 6,77 122 C10orf110 NR_024628 10 5,12E-20 1,32E-19 6,79 88 IDI2 NM_033261 10 5,66E-24 1,32E-19 0,00 84 IDI1 NM_004508 10 3,42E-56 1,51E-35 10,88 61 rs10794720* WDR37 NM_014023 10 8,53E-59 1,58E-42 8,66 53 NCRNA00200 NR_015376 10 1,92E-41 1,51E-35 0,00 50 ADARB2 NM_018702 10 1,00E+00 6,28E-13 5,65 624 PFKP NM_002627 10 3,04E-16 1,62E-14 12,13 1954 PITRM1 NM_014889 10 3,04E-16 7,41E-18 8,83 2059 FLRT1 NM_013280 11 1,00E+00 1,30E-09 6,84 593 STIP1 NM_006819 11 9,75E-03 3,44E-11 9,23 510 FERMT3 NM_031471 11 8,74E-09 3,44E-11 0,00 490 TRPT1 NM_001160393 11 8,74E-09 4,13E-08 0,00 471 VEGFB NM_003377 11 4,07E-07 1,30E-09 8,53 462 FKBP2 NM_004470 11 1,54E-05 7,67E-13 9,49 456 PPP1R14B NM_138689 11 9,75E-03 7,67E-13 10,19 450 PLCB3 NM_000932 11 4,52E-04 7,67E-13 7,86 445 C11orf20 NM_001039496 11 1,54E-05 2,34E-16 0,00 396 ESRRA NM_004451 11 4,07E-07 3,22E-18 8,60 391 TRMT112 NM_016404 11 1,56E-10 3,22E-18 11,03 379 PRDX5 NM_012094 11 1,56E-10 3,22E-18 0,00 379 CCDC88B NM_032251 11 3,08E-14 3,74E-22 0,00 356 RPS6KA4 NM_001006944 11 3,08E-14 3,74E-22 9,02 337 SLC22A11 NM_018484 11 5,90E-29 6,35E-36 6,06 141 SLC22A12 NM_144585 11 1,05E-26 2,24E-33 0,00 106 NRXN2 NM_138734 11 1,37E-33 1,68E-41 6,46 53 RASGRP2 NM_001098671 11 2,20E-62 1,68E-41 6,59 48 PYGM NM_001164716 11 7,02E-41 1,68E-41 6,81 64 SF1 NM_201995 11 7,02E-41 1,68E-41 10,77 82 rs504915** MAP4K2 NM_004579 11 2,40E-22 3,22E-18 6,24 107 MEN1 NM_130800 11 3,48E-18 3,77E-20 9,02 114 CDC42BPG NM_017525 11 3,48E-18 2,34E-16 0,00 148 EHD1 NM_006795 11 8,74E-09 1,30E-09 7,76 182 MIR192 NR_029578 11 4,07E-07 7,67E-13 0,00 195 MIR194-2 NR_029829 11 4,07E-07 7,67E-13 0,00 195 ATG2A NM_015104 11 8,74E-09 3,44E-11 9,25 221 PPP2R5B NM_006244 11 8,74E-09 4,13E-08 8,73 228 GPHA2 NM_130769 11 2,36E-12 4,13E-08 0,00 239 C11orf85 NM_001037225 11 2,36E-12 4,13E-08 0,00 264 BATF2 NM_138456 11 8,74E-09 7,67E-13 0,00 300 ARL2 NM_001667 11 8,74E-09 3,22E-18 10,18 318 SNX15 NM_013306 11 8,74E-09 3,77E-20 7,91 331 SAC3D1 NM_013299 11 4,52E-04 2,34E-16 7,79 344 CDCA5 NM_080668 11 8,74E-09 3,44E-11 0,00 388 ZFPL1 NM_006782 11 8,74E-09 3,44E-11 8,26 388 C11orf2 NM_013265 11 8,74E-09 4,13E-08 10,00 400 TM7SF2 NM_003273 11 4,07E-07 3,44E-11 9,28 415 ZNHIT2 NM_014205 11 1,54E-05 3,44E-11 7,79 421 FAU NM_001997 11 1,54E-05 3,44E-11 12,72 426 CORO1C NM_014325 12 2,64E-09 2,47E-03 11,04 2882

rs653178 ARPC3 NM_005719 12 2,64E-09 1,47E-04 11,04 1120 GPN3 NM_016301 12 2,64E-09 6,73E-06 8,15 1102 PPP1CC NM_002710 12 2,64E-09 2,47E-03 10,24 827 FAM109A NM_144671 12 2,16E-16 1,24E-17 0,00 201 SH2B3 NM_005475 12 2,16E-16 9,73E-16 8,13 164 ATXN2 NM_002973 12 5,17E-53 1,84E-46 8,57 30 BRAP NM_006768 12 3,72E-49 1,31E-39 5,13 116 rs653178 ACAD10 NM_001136542 12 3,72E-49 1,31E-39 8,29 116 ALDH2 NM_000690 12 4,84E-85 1,53E-56 9,77 197 MAPKAPK5 NM_003668 12 6,19E-91 1,65E-53 8,64 273 C12orf47 NR_015404 12 6,19E-91 1,65E-53 7,89 273 TMEM116 NM_138341 12 1,04E-12 1,63E-18 0,00 443 ERP29 NM_001034025 12 1,04E-12 1,63E-18 11,68 443 C12orf30 NM_024953 12 2,64E-09 1,55E-12 0,00 539 TRAFD1 NM_001143906 12 5,70E-11 6,50E-14 7,83 556 C12orf51 NM_001109662 12 1,02E-07 7,27E-09 8,28 736 DACH1 NM_004392 13 8,25E-40 7,08E-35 4,87 94 C13orf37 NM_001071775 13 4,93E-16 4,55E-14 0,00 954 rs626277 C13orf34 NM_024808 13 4,93E-16 4,55E-14 6,73 954 PIBF1 NM_006346 13 3,37E-11 4,35E-08 7,69 1009 DIS3 NM_001128226 13 3,37E-11 4,35E-08 5,07 1009 C15orf43 NM_152448 15 1,94E-13 3,08E-16 0,00 392 SORD NM_003104 15 4,45E-15 1,17E-14 8,76 326 DUOX2 NM_014080 15 7,40E-12 2,10E-21 5,96 235 DUOXA2 NM_207581 15 7,40E-12 2,10E-21 0,00 235 DUOXA1 NM_144565 15 4,45E-15 6,91E-18 0,00 219 DUOX1 NM_017434 15 4,45E-15 6,91E-18 5,88 219 SHF NM_138356 15 4,42E-26 7,86E-32 0,00 148 SLC28A2 NM_004212 15 1,49E-41 3,39E-37 6,03 97 rs2453533* GATM NM_001482 15 3,39E-52 2,36E-34 6,32 30 SPATA5L1 NM_024063 15 1,49E-41 2,36E-34 8,21 53 C15orf48 NM_032413 15 8,95E-17 6,91E-18 0,00 82 MIR147B NR_030599 15 4,45E-15 6,91E-18 0,00 84 C15orf21 NR_022014 15 8,95E-17 3,08E-16 0,00 162 SLC30A4 NM_013309 15 7,40E-12 3,08E-16 5,30 174 PLDN NM_012388 15 6,99E-09 6,91E-18 0,00 238 SQRDL NM_021199 15 6,99E-09 3,81E-13 12,12 286 KIAA1370 NM_019600 15 2,57E-07 1,33E-11 0,00 937 ONECUT1 NM_004498 15 7,03E-12 3,72E-16 6,26 826 rs17730436* WDR72 NM_182758 15 1,95E-27 2,22E-21 0,00 144 UNC13C NM_001080534 15 2,09E-14 4,74E-13 0,00 397 WWOX NM_130844 16 8,66E-08 7,64E-14 8,97 1512 rs889472 MAF NM_005360 16 7,30E-61 2,48E-34 7,06 11 DYNLRB2 NM_130897 16 2,31E-13 4,82E-11 0,00 929 PRPF40A NM_017892 2 5,34E-10 5,52E-09 10,01 39595 ARL6IP6 NM_152522 2 5,34E-10 5,52E-09 0,00 39595 rs11123170*** RPRM NM_019845 2 5,52E-07 4,60E-12 7,39 40356 GALNT13 NM_052917 2 8,25E-19 3,53E-25 0,00 40749 KCNJ3 NM_002239 2 8,29E-23 4,78E-21 5,94 41576 APPBP2 NM_006380 17 1,49E-06 1,03E-10 8,59 636 BCAS3 NM_001099432 17 3,31E-25 3,32E-25 8,06 484 TBX2 NM_005994 17 4,66E-59 6,19E-45 7,79 238 C17orf82 NM_203425 17 2,07E-31 4,87E-39 0,00 250 rs11868441*** TBX4 NM_018488 17 6,74E-16 3,32E-25 7,13 295 NACA2 NM_199290 17 4,26E-38 2,84E-27 4,32 429 BRIP1 NM_032043 17 1,50E-12 8,39E-14 4,89 702 INTS2 NM_020748 17 6,00E-08 1,03E-10 0,00 766 MED13 NM_005121 17 1,32E-06 1,14E-09 8,62 903 BCAS3 NM_001099432 17 3,31E-25 3,32E-25 8,06 701 TBX2 NM_005994 17 4,66E-59 6,19E-45 7,79 21 C17orf82 NM_203425 17 2,07E-31 4,87E-39 0,00 33 rs9895661 TBX4 NM_018488 17 6,74E-16 3,32E-25 7,13 77 NACA2 NM_199290 17 4,26E-38 2,84E-27 4,32 212 BRIP1 NM_032043 17 1,50E-12 8,39E-14 4,89 484 MED13 NM_005121 17 1,32E-06 1,14E-09 8,62 686 SETBP1 NM_001130110 18 1,15E-03 2,49E-10 8,18 927 SLC14A2 NM_007163 18 5,63E-60 3,22E-34 6,31 8 SLC14A1 NM_001128588 18 6,65E-13 4,77E-21 8,43 117 rs7227483*** SIGLEC15 NM_213602 18 9,38E-05 1,69E-14 10,30 218 rs7227483*** KIAA1632 NM_020964 18 3,41E-07 2,49E-10 0,00 360 PSTPIP2 NM_024430 18 1,59E-08 1,69E-14 7,59 465 LOXHD1 NM_001145472 18 1,00E+00 1,69E-14 0,00 952 DKFZp566F0947 NR_026894 19 5,47E-03 6,42E-18 0,00 1716 ZNF507 NM_001136156 19 6,63E-05 2,65E-16 6,84 520 DPY19L3 NM_207325 19 3,65E-07 7,09E-12 0,00 460 PDCD5 NM_004708 19 4,34E-11 2,20E-21 0,00 285 ANKRD27 NM_032139 19 1,18E-20 3,30E-25 8,28 191 RGS9BP NM_207391 19 1,18E-20 3,30E-25 0,00 191 NUDT19 NM_001105570 19 2,32E-24 3,30E-25 0,00 174 TDRD12 NM_001110822 19 1,74E-30 2,75E-27 6,95 146 SLC7A9 NM_001126335 19 3,28E-40 1,15E-34 6,32 4 rs12460876 CCDC123 NM_032816 19 2,32E-24 3,02E-23 0,00 106 C19orf40 NM_152266 19 2,32E-24 3,02E-23 6,61 106 RHPN2 NM_033103 19 2,10E-08 7,09E-12 0,00 199 GPATCH1 NM_018025 19 3,65E-07 2,93E-09 6,20 215 WDR88 NM_173479 19 1,58E-12 1,31E-19 0,00 266 LRP3 NM_002333 19 6,63E-05 1,55E-10 7,59 329 SLC7A10 NM_019849 19 1,03E-09 1,55E-10 6,27 360 CEBPG NM_001806 19 4,99E-14 2,77E-13 8,62 508 KCTD15 NM_024076 19 3,65E-07 2,93E-09 7,18 931 C20orf108 NM_080821 20 4,53E-05 1,89E-15 6,10 2535 AURKA NM_003600 20 6,41E-10 5,30E-14 8,03 2502 C20orf43 NM_016407 20 6,41E-10 9,52E-04 9,04 2425 BMP7 NM_001719 20 4,53E-05 5,13E-10 8,17 1627 RAE1 NM_003610 20 3,53E-06 8,29E-09 8,89 1543 PMEPA1 NM_020182 20 6,41E-10 1,16E-07 9,67 1184 PPP4R1L NR_003505 20 6,31E-28 1,57E-18 0,00 585 RAB22A NM_020673 20 6,31E-28 1,57E-18 8,15 584 VAPB NM_004738 20 2,16E-22 3,62E-20 9,62 505 APCDD1L NM_153360 20 1,31E-08 1,89E-15 0,00 379 STX16 NM_001001433 20 5,86E-34 5,84E-17 6,79 243 NPEPL1 NM_024663 20 3,36E-14 5,84E-17 8,69 201 MIR296 NR_029844 20 2,53E-17 3,62E-20 0,00 76 rs6026584 MIR298 NR_030580 20 2,53E-17 3,62E-20 0,00 76 GNAS NM_016592 20 2,16E-22 1,20E-23 12,75 54 GNASAS NR_002785 20 6,31E-28 7,15E-22 0,00 43 TH1L NM_198976 20 6,32E-43 2,04E-36 9,77 87 CTSZ NM_001336 20 1,44E-40 6,27E-34 8,02 113 TUBB1 NM_030773 20 9,55E-57 3,21E-39 5,52 125 ATP5E NM_006886 20 9,55E-57 3,21E-39 11,66 138 SLMO2 NM_016045 20 6,08E-48 6,27E-34 6,86 149 ZNF831 NM_178457 20 6,41E-10 3,62E-20 0,00 297 EDN3 NM_207032 20 4,83E-04 1,30E-12 5,48 406 SYCP2 NM_014258 20 2,33E-07 5,13E-10 4,16 1038 PPP1R3D NM_006242 20 2,33E-07 5,13E-10 6,53 1046 C20orf177 NM_022106 20 2,33E-07 5,13E-10 0,00 1046 SSTR4 NM_001052 20 9,15E-09 2,94E-13 7,21 597 THBD NM_000361 20 9,15E-09 2,65E-09 7,95 582 NXT1 NM_013248 20 1,05E-35 8,19E-23 9,00 281 GZF1 NM_022482 20 8,76E-38 1,56E-28 0,00 268 NAPB NM_022080 20 6,49E-40 3,61E-35 0,00 211 CSTL1 NM_138283 20 6,49E-40 3,61E-35 0,00 192 CST11 NM_080830 20 1,05E-35 3,61E-35 0,00 179 CST8 NM_005492 20 5,07E-26 9,42E-18 6,84 141 CSTT NR_001279 20 9,41E-21 2,25E-19 0,00 113 CST9L NM_080610 20 9,33E-30 1,27E-30 0,00 63 CST9 NM_001008693 20 5,82E-54 7,98E-33 0,00 26 CST3 NM_000099 20 2,72E-59 1,47E-40 12,07 6 rs911119 CST4 NM_001899 20 6,49E-40 1,52E-26 7,17 57 CST1 NM_001898 20 1,83E-17 8,19E-23 5,63 119 CST2 NM_001322 20 6,95E-13 3,41E-16 7,97 195 CST5 NM_001900 20 2,31E-14 2,94E-13 6,76 248 GGTLC1 NM_178312 20 1,66E-07 2,65E-09 9,01 355 TMEM90B NM_024893 20 1,00E+00 1,46E-10 6,87 837 C20orf3 NM_020531 20 4,40E-10 4,16E-08 10,53 1361 ACSS1 NM_032501 20 3,43E-03 2,65E-09 0,00 1427 ENTPD6 NM_001114089 20 4,40E-10 1,46E-10 9,30 1564 PYGB NM_002862 20 6,86E-16 2,65E-09 10,72 1616 rs911119

ABHD12 NM_015600 20 4,40E-10 5,35E-04 0,00 1759 GINS1 NM_021067 20 9,15E-09 6,46E-05 7,86 1776 Supplemental table 6: Pathway analysis based on CKD candidate genes retrieved with 4C-seq in HRGECs.

Ingenuity Canonical Pathways -log(p-value) Ratio Molecules Trans, trans-farnesyl Diphosphate Biosynthesis 5.18 0.60 FDPS,IDI2,IDI1 Superpathway of Geranylgeranyldiphosphate Biosynthesis I (via Mevalonate) 3.38 0.18 FDPS,IDI2,IDI1 Superpathway of Cholesterol Biosynthesis 2.73 0.11 FDPS,IDI2,IDI1 Mevalonate Pathway I 2.25 0.15 IDI2,IDI1 Phagosome Maturation 2.04 0.03 CTSZ,CTSK,CTSS,STX16,NAPB Amyloid Processing 1.99 0.06 CAPN11,APH1A,PRKAG2 autophagy 1.80 0.05 CTSZ,CTSK,CTSS mTOR Signaling 1.50 0.03 VEGFA,RHEB,PRKAG2,RPS6KA4,RICTOR Phenylethylamine Degradation I 1.46 0.25 ALDH2 Geranylgeranyldiphosphate Biosynthesis 1.46 0.25 FDPS Melanocyte Development and Pigmentation Signaling 1.29 0.03 GNAS,PRKAG2,RPS6KA4 Glycerol Degradation I 1.29 0.17 GK5 Tight Junction Signaling 1.22 0.02 PRKAG2,STX16,CNKSR3,NAPB VEGF Signaling 1.20 0.03 VEGFA,EIF2B4,ARNT Corticotropin Releasing Hormone Signaling 1.13 0.03 VEGFA,GNAS,PRKAG2 AMPK Signaling 1.06 0.02 GNAS,PRKAG2,PFKP,PPM1G Gαi Signaling 1.05 0.03 GNAS,PRKAG2,RGS14 3-phosphoinositide Biosynthesis 1.03 0.02 PIP5K1A,DUSP11,PPM1K,PTPN12 Dolichyl-diphosphooligosaccharide Biosynthesis 1.03 0.09 DPM3 ILK Signaling 1.02 0.02 VEGFA,MUC1,RPS6KA4,RICTOR Assembly of RNA Polymerase III Complex 0.96 0.08 GTF3C2 Hypoxia Signaling in the Cardiovascular System 0.95 0.03 VEGFA,ARNT Phenylalanine Degradation IV (Mammalian, via Side Chain) 0.93 0.07 ALDH2 D-myo-inositol (1,4,5,6)-Tetrakisphosphate Biosynthesis 0.89 0.02 DUSP11,PPM1K,PTPN12 D-myo-inositol (3,4,5,6)-tetrakisphosphate Biosynthesis 0.89 0.02 DUSP11,PPM1K,PTPN12 Extrinsic Prothrombin Activation Pathway 0.88 0.06 F12 GPCR-Mediated Integration of Enteroendocrine Signaling Exemplified by an L Cell 0.88 0.03 GNAS,PRKAG2 Ubiquinol-10 Biosynthesis (Eukaryotic) 0.86 0.06 ECHDC1 GDNF Family Ligand-Receptor Interactions 0.84 0.03 PDLIM7,DOK3 Superpathway of Inositol Phosphate Compounds 0.84 0.02 PIP5K1A,DUSP11,PPM1K,PTPN12 Role of BRCA1 in DNA Damage Response 0.82 0.03 FAAP24,ATR Relaxin Signaling 0.82 0.02 VEGFA,GNAS,PRKAG2 GADD45 Signaling 0.81 0.05 ATR Histamine Degradation 0.81 0.05 ALDH2 DNA damage-induced 14-3-3σ Signaling 0.81 0.05 ATR eNOS Signaling 0.81 0.02 VEGFA,GNAS,PRKAG2 3-phosphoinositide Degradation 0.81 0.02 DUSP11,PPM1K,PTPN12 Renal Cell Carcinoma Signaling 0.80 0.02 VEGFA,ARNT Huntington's Disease Signaling 0.79 0.02 CAPN11,DCTN1,STX16,NAPB D-myo-inositol-5-phosphate Metabolism 0.78 0.02 DUSP11,PPM1K,PTPN12 Oxidative Ethanol Degradation III 0.77 0.05 ALDH2 GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells 0.76 0.02 GNAS,PRKAG2 Role of Lipids/Lipid Rafts in the Pathogenesis of Influenza 0.75 0.05 FDPS Fatty Acid α-oxidation 0.75 0.05 ALDH2 α-Adrenergic Signaling 0.75 0.02 GNAS,PRKAG2 G Beta Gamma Signaling 0.74 0.02 GNAS,PRKAG2 Putrescine Degradation III 0.74 0.04 ALDH2 Apoptosis Signaling 0.73 0.02 CAPN11,MCL1 Gap Junction Signaling 0.73 0.02 DBN1,GNAS,PRKAG2 IL-1 Signaling 0.72 0.02 GNAS,PRKAG2 Ephrin Receptor Signaling 0.70 0.02 VEGFA,GNAS,EFNA1 Tryptophan Degradation X (Mammalian, via Tryptamine) 0.70 0.04 ALDH2 Glycolysis I 0.70 0.04 PFKP Ethanol Degradation IV 0.70 0.04 ALDH2 D-myo-inositol (1,4,5)-Trisphosphate Biosynthesis 0.67 0.04 PIP5K1A CDK5 Signaling 0.66 0.02 GNAS,PRKAG2 Intrinsic Prothrombin Activation Pathway 0.65 0.03 F12 Sonic Hedgehog Signaling 0.63 0.03 PRKAG2 RAR Activation 0.63 0.02 VEGFA,NSD1,PRKAG2 G Protein Signaling Mediated by Tubby 0.61 0.03 GNAS Gαs Signaling 0.60 0.02 GNAS,PRKAG2 Amyotrophic Lateral Sclerosis Signaling 0.59 0.02 VEGFA,CAPN11 Androgen Signaling 0.59 0.02 GNAS,PRKAG2 Inhibition of Angiogenesis by TSP1 0.59 0.03 VEGFA Role of JAK2 in Hormone-like Cytokine Signaling 0.59 0.03 SH2B3 Nitric Oxide Signaling in the Cardiovascular System 0.58 0.02 VEGFA,PRKAG2 Coagulation System 0.57 0.03 F12 Dopamine Degradation 0.57 0.03 ALDH2 HIF1α Signaling 0.57 0.02 VEGFA,ARNT Ethanol Degradation II 0.55 0.03 ALDH2 Notch Signaling 0.54 0.03 APH1A RhoA Signaling 0.54 0.02 RHPN2,PIP5K1A Role of Tissue Factor in Cancer 0.54 0.02 VEGFA,RPS6KA4 Netrin Signaling 0.54 0.03 PRKAG2 tRNA Charging 0.54 0.03 TARS2 Neuroprotective Role of THOP1 in Alzheimer's Disease 0.53 0.03 PRKAG2 Noradrenaline and Adrenaline Degradation 0.53 0.03 ALDH2 PI3K/AKT Signaling 0.53 0.02 RHEB,MCL1 Sperm Motility 0.52 0.02 GNAS,PRKAG2 IL-6 Signaling 0.51 0.02 VEGFA,MCL1 UVC-Induced MAPK Signaling 0.51 0.02 ATR GNRH Signaling 0.50 0.02 GNAS,PRKAG2 Cellular Effects of Sildenafil (Viagra) 0.50 0.02 GNAS,PRKAG2 Role of IL-17F in Allergic Inflammatory Airway Diseases 0.49 0.02 RPS6KA4 Cardiac β-adrenergic Signaling 0.47 0.01 GNAS,PRKAG2 nNOS Signaling in Neurons 0.47 0.02 CAPN11 Cardiac Hypertrophy Signaling 0.47 0.01 EIF2B4,GNAS,PRKAG2 Aryl Hydrocarbon Receptor Signaling 0.46 0.01 ATR,ARNT TNFR1 Signaling 0.45 0.02 MAP4K2 Cell Cycle: G2/M DNA Damage Checkpoint Regulation 0.45 0.02 ATR Cancer Drug Resistance By Drug Efflux 0.45 0.02 ABCG2 Insulin Receptor Signaling 0.45 0.01 EIF2B4,PRKAG2 Hereditary Breast Cancer Signaling 0.45 0.01 FAAP24,ATR Ovarian Cancer Signaling 0.44 0.01 VEGFA,PRKAG2 Axonal Guidance Signaling 0.44 0.01 VEGFA,GNAS,PRKAG2,SEMA6C,EFNA1 Colorectal Cancer Metastasis Signaling 0.43 0.01 VEGFA,GNAS,PRKAG2 Phototransduction Pathway 0.43 0.02 PRKAG2 Role of CHK Proteins in Cell Cycle Checkpoint Control 0.41 0.02 ATR Regulation of Cellular Mechanics by Calpain Protease 0.40 0.02 CAPN11 MSP-RON Signaling Pathway 0.39 0.02 F12 Hepatic Cholestasis 0.39 0.01 MAP4K2,PRKAG2 Ephrin A Signaling 0.39 0.02 EFNA1 Retinoic acid Mediated Apoptosis Signaling 0.38 0.02 DAP3 Dopamine-DARPP32 Feedback in cAMP Signaling 0.38 0.01 GNAS,PRKAG2 Molecular Mechanisms of Cancer 0.38 0.01 GNAS,APH1A,PRKAG2,ATR CNTF Signaling 0.37 0.02 RPS6KA4 ERK5 Signaling 0.37 0.02 RPS6KA4 G-Protein Coupled Receptor Signaling 0.37 0.01 GNAS,PRKAG2,RGS14 Cell Cycle: G1/S Checkpoint Regulation 0.36 0.02 ATR PXR/RXR Activation 0.36 0.02 PRKAG2 Pyridoxal 5'-phosphate Salvage Pathway 0.36 0.02 GRK6 Mitochondrial Dysfunction 0.35 0.01 APH1A,ATP5E GABA Receptor Signaling 0.35 0.01 GNAS RhoGDI Signaling 0.35 0.01 PIP5K1A,GNAS Protein Kinase A Signaling 0.34 0.01 GNAS,PRKAG2,DUSP11,PTPN12 CCR5 Signaling in Macrophages 0.34 0.01 GNAS PPARα/RXRα Activation 0.33 0.01 GNAS,PRKAG2 Melatonin Signaling 0.33 0.01 PRKAG2 ErbB4 Signaling 0.33 0.01 APH1A T Helper Cell Differentiation 0.32 0.01 BCL6 Ephrin B Signaling 0.32 0.01 GNAS Serotonin Degradation 0.32 0.01 ALDH2 CREB Signaling in Neurons 0.32 0.01 GNAS,PRKAG2 BMP signaling pathway 0.31 0.01 PRKAG2 Dopamine Receptor Signaling 0.31 0.01 PRKAG2 Cyclins and Cell Cycle Regulation 0.30 0.01 ATR Role of NFAT in Cardiac Hypertrophy 0.30 0.01 GNAS,PRKAG2 ATM Signaling 0.29 0.01 ATR Growth Hormone Signaling 0.29 0.01 RPS6KA4 Clathrin-mediated Endocytosis Signaling 0.28 0.01 VEGFA,DAB2 IL-8 Signaling 0.28 0.01 VEGFA,GNAS ERK/MAPK Signaling 0.28 0.01 PRKAG2,RPS6KA4 FLT3 Signaling in Hematopoietic Progenitor Cells 0.28 0.01 RPS6KA4 Leptin Signaling in Obesity 0.28 0.01 PRKAG2 HIPPO signaling 0.27 0.01 MOB1A Breast Cancer Regulation by Stathmin1 0.27 0.01 GNAS,PRKAG2 Bladder Cancer Signaling 0.27 0.01 VEGFA VEGF Family Ligand-Receptor Interactions 0.27 0.01 VEGFA Regulation of Actin-based Motility by Rho 0.26 0.01 PIP5K1A Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes 0.25 0.01 PIP5K1A Salvage Pathways of Pyrimidine Ribonucleotides 0.25 0.01 GRK6 TR/RXR Activation 0.24 0.01 PFKP EIF2 Signaling 0.24 0.01 VEGFA,EIF2B4 FAK Signaling 0.23 0.01 CAPN11 cAMP-mediated signaling 0.23 0.01 GNAS,RGS14 UVA-Induced MAPK Signaling 0.23 0.01 RPS6KA4 Chronic Myeloid Leukemia Signaling 0.22 0.01 MECOM SAPK/JNK Signaling 0.22 0.01 MAP4K2 IGF-1 Signaling 0.22 0.01 PRKAG2 Oxidative Phosphorylation 0.21 0.01 ATP5E p53 Signaling 0.20 0.01 ATR Paxillin Signaling 0.20 0.01 PTPN12 Supplemental table 7: Pathway analysis based on CKD candidate genes retrieved with 4C-seq in HRPTECs.

Ingenuity Canonical Pathways -log(p-value) Ratio Molecules Superpathway of Geranylgeranyldiphosphate Biosynthesis I (via Mevalonate) 3.14 0.18 FDPS,PMVK,IDI1 Trans, trans-farnesyl Diphosphate Biosynthesis 2.96 0.40 FDPS,IDI1 Role of BRCA1 in DNA Damage Response 2.83 0.06 FAAP24,UIMC1,ATR,BABAM2,SMARCD3 Superpathway of Cholesterol Biosynthesis 2.49 0.11 FDPS,PMVK,IDI1 Melanocyte Development and Pigmentation Signaling 2.46 0.05 SHC1,GNAS,FGFR4,PRKAG2,RPS6KA4 Ephrin A Signaling 2.42 0.07 FGFR4,EFNA3,EFNA4,EFNA1 Pathogenesis of Multiple Sclerosis 2.41 0.22 CXCL10,CXCL9 AMPK Signaling 2.37 0.04 GNAS,FGFR4,PRKAG2,PRKAA1,PFKP,SMARCD3,PPM1G VEGF Signaling 2.31 0.05 VEGFA,SHC1,EIF2B4,FGFR4,ACTG2 eNOS Signaling 2.19 0.04 VEGFA,GNAS,HSP90AB1,FGFR4,PRKAG2,PRKAA1 Glycogen Degradation II 2.16 0.17 PYGM,PYGB Nitric Oxide Signaling in the Cardiovascular System 2.14 0.04 VEGFA,HSP90AB1,FGFR4,PRKAG2,PRKAA1 Mevalonate Pathway I 2.09 0.15 PMVK,IDI1 GDNF Family Ligand-Receptor Interactions 2.05 0.05 SHC1,PDLIM7,FGFR4,DOK3 Glycogen Degradation III 2.02 0.14 PYGM,PYGB PI3K/AKT Signaling 1.97 0.04 SHC1,RHEB,HSP90AB1,NFKBIE,MCL1 Sorbitol Degradation I 1.97 1.00 SORD Ephrin Receptor Signaling 1.96 0.03 VEGFA,SHC1,GNAS,EFNA3,EFNA4,EFNA1 Type II Diabetes Mellitus Signaling 1.93 0.04 PKLR,NFKBIE,FGFR4,PRKAG2,PRKAA1 IL-6 Signaling 1.93 0.04 VEGFA,SHC1,NFKBIE,FGFR4,MCL1 PPARα/RXRα Activation 1.91 0.03 SHC1,GNAS,HSP90AB1,NFKBIE,PRKAG2,PRKAA1 Extrinsic Prothrombin Activation Pathway 1.91 0.13 F12,THBD α-Adrenergic Signaling 1.85 0.05 GNAS,PYGM,PRKAG2,PYGB Cell Cycle: G2/M DNA Damage Checkpoint Regulation 1.81 0.06 CKS1B,ATR,AURKA Amyloid Processing 1.77 0.06 CAPN11,APH1A,PRKAG2 NRF2-mediated Oxidative Stress Response 1.76 0.03 ERP29,SOD2,FGFR4,MAF,CCT7,ACTG2 Prostate Cancer Signaling 1.74 0.04 HSP90AB1,NFKBIE,FGFR4,NKX3-1 mTOR Signaling 1.70 0.03 VEGFA,RHEB,FGFR4,PRKAG2,PRKAA1,RPS6KA4 Flavin Biosynthesis IV (Mammalian) 1.67 0.50 FLAD1 Glycine Degradation (Creatine Biosynthesis) 1.67 0.50 GATM Axonal Guidance Signaling 1.64 0.02 VEGFA,SHC1,GNAS,ADAM15,FGFR4,EFNA3,PRKAG2,SEMA6C,EFNA4,EFNA1 Relaxin Signaling 1.63 0.03 VEGFA,GNAS,NFKBIE,FGFR4,PRKAG2 MSP-RON Signaling Pathway 1.60 0.05 F12,FGFR4,ACTG2 autophagy 1.58 0.05 CTSZ,CTSK,CTSS G-Protein Coupled Receptor Signaling 1.57 0.03 SHC1,GNAS,NFKBIE,FGFR4,PRKAG2,DRD5,RGS14 Glycolysis I 1.54 0.08 PKLR,PFKP Corticotropin Releasing Hormone Signaling 1.51 0.04 VEGFA,GNAS,UCN,PRKAG2 EIF2 Signaling 1.50 0.03 VEGFA,SHC1,EIF2B4,FGFR4,RPL37,ACTG2 Hypoxia Signaling in the Cardiovascular System 1.49 0.05 VEGFA,HSP90AB1,NFKBIE Gap Junction Signaling 1.47 0.03 DBN1,GNAS,FGFR4,PRKAG2,ACTG2 Glucocorticoid Receptor Signaling 1.46 0.02 SHC1,HSP90AB1,NFKBIE,FGFR4,PRKAG2,PRKAA1,SMARCD3 Intrinsic Prothrombin Activation Pathway 1.42 0.07 F12,THBD Gαi Signaling 1.40 0.03 SHC1,GNAS,PRKAG2,RGS14 ErbB4 Signaling 1.38 0.04 SHC1,APH1A,FGFR4 Phenylethylamine Degradation I 1.38 0.25 ALDH2 Geranylgeranyldiphosphate Biosynthesis 1.38 0.25 FDPS Molecular Mechanisms of Cancer 1.32 0.02 SHC1,GNAS,APH1A,NFKBIE,FGFR4,PRKAG2,ATR,AURKA Cellular Effects of Sildenafil (Viagra) 1.30 0.03 SLC4A5,GNAS,PRKAG2,ACTG2 Role of JAK2 in Hormone-like Cytokine Signaling 1.30 0.06 SHC1,SH2B3 Erythropoietin Signaling 1.28 0.04 SHC1,NFKBIE,FGFR4 Coagulation System 1.27 0.06 F12,THBD Growth Hormone Signaling 1.26 0.04 FGFR4,RPS6KA4,ONECUT1 ILK Signaling 1.23 0.03 VEGFA,FGFR4,MUC1,RPS6KA4,ACTG2 Small Cell Lung Cancer Signaling 1.22 0.04 NFKBIE,FGFR4,CKS1B PEDF Signaling 1.22 0.04 SOD2,NFKBIE,FGFR4 ERK/MAPK Signaling 1.21 0.03 SHC1,FGFR4,PRKAG2,MAPKAPK5,RPS6KA4 FLT3 Signaling in Hematopoietic Progenitor Cells 1.20 0.04 SHC1,FGFR4,RPS6KA4 Insulin Receptor Signaling 1.19 0.03 SHC1,EIF2B4,FGFR4,PRKAG2 Hereditary Breast Cancer Signaling 1.18 0.03 FGFR4,FAAP24,ATR,SMARCD3 G Beta Gamma Signaling 1.17 0.03 SHC1,GNAS,PRKAG2 VEGF Family Ligand-Receptor Interactions 1.17 0.03 VEGFA,SHC1,FGFR4 Phagosome Maturation 1.17 0.03 CTSZ,CTSK,CTSS,STX16 Apoptosis Signaling 1.16 0.03 CAPN11,NFKBIE,MCL1 IL-1 Signaling 1.13 0.03 GNAS,NFKBIE,PRKAG2 Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes 1.11 0.03 PIP5K1A,ACTG2,FYB PPAR Signaling 1.11 0.03 SHC1,HSP90AB1,NFKBIE Role of IL-17F in Allergic Inflammatory Airway Diseases 1.10 0.05 CXCL10,RPS6KA4 Superoxide Radicals Degradation 1.09 0.13 SOD2 Glycoaminoglycan-protein Linkage Region Biosynthesis 1.09 0.13 B4GALT7 CDK5 Signaling 1.05 0.03 GNAS,PRKAG2,DRD5 FAK Signaling 1.05 0.03 CAPN11,FGFR4,ACTG2 Hepatic Cholestasis 1.04 0.03 MAP4K2,NFKBIE,FGFR4,PRKAG2 TNFR1 Signaling 1.02 0.04 MAP4K2,NFKBIE SAPK/JNK Signaling 1.00 0.03 MAP4K2,SHC1,FGFR4 IGF-1 Signaling 0.98 0.03 SHC1,FGFR4,PRKAG2 FcγRIIB Signaling in B Lymphocytes 0.96 0.04 SHC1,FGFR4 Gαs Signaling 0.96 0.03 GNAS,PRKAG2,DRD5 Dolichyl-diphosphooligosaccharide Biosynthesis 0.95 0.09 DPM3 Amyotrophic Lateral Sclerosis Signaling 0.94 0.03 VEGFA,CAPN11,FGFR4 Androgen Signaling 0.94 0.03 SHC1,GNAS,PRKAG2 Telomerase Signaling 0.94 0.03 SHC1,HSP90AB1,FGFR4 Paxillin Signaling 0.92 0.03 FGFR4,ACTG2,PTPN12 Protein Kinase A Signaling 0.90 0.02 GNAS,PYGM,NFKBIE,PRKAG2,DUSP11,PYGB,PTPN12 NGF Signaling 0.89 0.03 SHC1,FGFR4,RPS6KA4 Assembly of RNA Polymerase III Complex 0.89 0.08 GTF3C2 CREB Signaling in Neurons 0.87 0.02 SHC1,GNAS,FGFR4,PRKAG2 B Cell Receptor Signaling 0.87 0.02 SHC1,NFKBIE,FGFR4,BCL6 Renin-Angiotensin Signaling 0.87 0.03 SHC1,FGFR4,PRKAG2 fMLP Signaling in Neutrophils 0.86 0.02 GNAS,NFKBIE,FGFR4 Phenylalanine Degradation IV (Mammalian, via Side Chain) 0.86 0.07 ALDH2 Activation of IRF by Cytosolic Pattern Recognition Receptors 0.85 0.03 NFKBIE,ADAR iCOS-iCOSL Signaling in T Helper Cells 0.85 0.02 SHC1,NFKBIE,FGFR4 Role of Tissue Factor in Cancer 0.85 0.02 VEGFA,FGFR4,RPS6KA4 CNTF Signaling 0.84 0.03 FGFR4,RPS6KA4 RAR Activation 0.84 0.02 VEGFA,NSD1,PRKAG2,SMARCD3 IL-2 Signaling 0.83 0.03 SHC1,FGFR4 Role of NFAT in Cardiac Hypertrophy 0.83 0.02 SHC1,GNAS,FGFR4,PRKAG2 Thrombopoietin Signaling 0.82 0.03 SHC1,FGFR4 Pyridoxal 5'-phosphate Salvage Pathway 0.82 0.03 GRK6,PRKAA1 3-phosphoinositide Biosynthesis 0.82 0.02 PIP5K1A,FGFR4,DUSP11,PTPN12 Clathrin-mediated Endocytosis Signaling 0.80 0.02 VEGFA,FGFR4,DAB2,ACTG2 Role of IL-17A in Arthritis 0.80 0.03 NFKBIE,FGFR4 EGF Signaling 0.79 0.03 SHC1,FGFR4 Ubiquinol-10 Biosynthesis (Eukaryotic) 0.78 0.06 ECHDC1 Agrin Interactions at Neuromuscular Junction 0.78 0.03 PKLR,ACTG2 ErbB2-ErbB3 Signaling 0.78 0.03 SHC1,FGFR4 Myc Mediated Apoptosis Signaling 0.77 0.03 SHC1,FGFR4 Breast Cancer Regulation by Stathmin1 0.77 0.02 SHC1,GNAS,FGFR4,PRKAG2 Role of JAK1 and JAK3 in γc Cytokine Signaling 0.76 0.03 SHC1,FGFR4 GPCR-Mediated Integration of Enteroendocrine Signaling Exemplified by an L Cell 0.75 0.03 GNAS,PRKAG2 GM-CSF Signaling 0.74 0.03 SHC1,FGFR4 GADD45 Signaling 0.74 0.05 ATR Histamine Degradation 0.74 0.05 ALDH2 DNA damage-induced 14-3-3σ Signaling 0.74 0.05 ATR IL-15 Signaling 0.71 0.03 SHC1,FGFR4 Role of PI3K/AKT Signaling in the Pathogenesis of Influenza 0.71 0.03 NFKBIE,FGFR4 Neurotrophin/TRK Signaling 0.71 0.03 SHC1,FGFR4 Angiopoietin Signaling 0.70 0.03 NFKBIE,FGFR4 IL-17A Signaling in Airway Cells 0.70 0.03 NFKBIE,FGFR4 Dopamine Receptor Signaling 0.70 0.03 PRKAG2,DRD5 Ovarian Cancer Signaling 0.70 0.02 VEGFA,FGFR4,PRKAG2 Maturity Onset Diabetes of Young (MODY) Signaling 0.70 0.05 PKLR Oxidative Ethanol Degradation III 0.70 0.05 ALDH2 VDR/RXR Activation 0.70 0.03 CXCL10,THBD CD40 Signaling 0.70 0.03 NFKBIE,FGFR4 Integrin Signaling 0.69 0.02 SHC1,CAPN11,FGFR4,ACTG2 Role of Lipids/Lipid Rafts in the Pathogenesis of Influenza 0.68 0.05 FDPS Fatty Acid α-oxidation 0.68 0.05 ALDH2 Renal Cell Carcinoma Signaling 0.67 0.02 VEGFA,FGFR4 Th2 Pathway 0.67 0.02 APH1A,FGFR4,MAF Putrescine Degradation III 0.66 0.04 ALDH2 IL-3 Signaling 0.66 0.02 SHC1,FGFR4 Prolactin Signaling 0.66 0.02 SHC1,FGFR4 JAK/Stat Signaling 0.66 0.02 SHC1,FGFR4 Actin Cytoskeleton Signaling 0.65 0.02 SHC1,PIP5K1A,FGFR4,ACTG2 IL-17 Signaling 0.64 0.02 CXCL10,FGFR4 Leptin Signaling in Obesity 0.64 0.02 FGFR4,PRKAG2 GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells 0.64 0.02 GNAS,PRKAG2 Superpathway of Inositol Phosphate Compounds 0.64 0.02 PIP5K1A,FGFR4,DUSP11,PTPN12 LPS-stimulated MAPK Signaling 0.63 0.02 NFKBIE,FGFR4 NF-κB Activation by Viruses 0.63 0.02 NFKBIE,FGFR4 Regulation of eIF4 and p70S6K Signaling 0.63 0.02 SHC1,EIF2B4,FGFR4 IL-17A Signaling in Gastric Cells 0.63 0.04 CXCL10 Tryptophan Degradation X (Mammalian, via Tryptamine) 0.63 0.04 ALDH2 Ethanol Degradation IV 0.63 0.04 ALDH2 Neuregulin Signaling 0.62 0.02 SHC1,HSP90AB1 Cardiac Hypertrophy Signaling 0.62 0.02 EIF2B4,GNAS,FGFR4,PRKAG2 Gαq Signaling 0.61 0.02 GNAS,NFKBIE,FGFR4 IL-4 Signaling 0.61 0.02 SHC1,FGFR4 Dopamine-DARPP32 Feedback in cAMP Signaling 0.60 0.02 GNAS,PRKAG2,DRD5 PDGF Signaling 0.60 0.02 SHC1,FGFR4 D-myo-inositol (1,4,5)-Trisphosphate Biosynthesis 0.60 0.04 PIP5K1A Regulation of Actin-based Motility by Rho 0.60 0.02 PIP5K1A,ACTG2 Huntington's Disease Signaling 0.59 0.02 SHC1,CAPN11,FGFR4,STX16 Death Receptor Signaling 0.59 0.02 NFKBIE,ACTG2 Aldosterone Signaling in Epithelial Cells 0.59 0.02 PIP5K1A,HSP90AB1,FGFR4 Tight Junction Signaling 0.58 0.02 PRKAG2,STX16,ACTG2 TNFR2 Signaling 0.57 0.03 NFKBIE Glutathione-mediated Detoxification 0.57 0.03 NAT8 Salvage Pathways of Pyrimidine Ribonucleotides 0.57 0.02 GRK6,PRKAA1 Acute Phase Response Signaling 0.57 0.02 SHC1,SOD2,NFKBIE Colorectal Cancer Metastasis Signaling 0.57 0.02 VEGFA,GNAS,FGFR4,PRKAG2 Signaling by Rho Family GTPases 0.57 0.02 PIP5K1A,GNAS,FGFR4,ACTG2 Tec Kinase Signaling 0.57 0.02 GNAS,FGFR4,ACTG2 Mitochondrial Dysfunction 0.56 0.02 SOD2,APH1A,ATP5E Sonic Hedgehog Signaling 0.56 0.03 PRKAG2 RhoGDI Signaling 0.55 0.02 PIP5K1A,GNAS,ACTG2 TR/RXR Activation 0.55 0.02 FGFR4,PFKP ErbB Signaling 0.55 0.02 SHC1,FGFR4 4-1BB Signaling in T Lymphocytes 0.55 0.03 NFKBIE G Protein Signaling Mediated by Tubby 0.54 0.03 GNAS PAK Signaling 0.53 0.02 SHC1,FGFR4 RANK Signaling in Osteoclasts 0.53 0.02 NFKBIE,FGFR4 Sertoli Cell-Sertoli Cell Junction Signaling 0.53 0.02 TJAP1,PRKAG2,ACTG2 Virus Entry via Endocytic Pathways 0.53 0.02 FGFR4,ACTG2 UVA-Induced MAPK Signaling 0.53 0.02 FGFR4,RPS6KA4 MIF-mediated Glucocorticoid Regulation 0.53 0.03 NFKBIE Chronic Myeloid Leukemia Signaling 0.52 0.02 MECOM,FGFR4 Oncostatin M Signaling 0.52 0.03 SHC1 TWEAK Signaling 0.52 0.03 NFKBIE Inhibition of Angiogenesis by TSP1 0.52 0.03 VEGFA IL-17A Signaling in Fibroblasts 0.51 0.03 NFKBIE Dopamine Degradation 0.51 0.03 ALDH2 Role of NFAT in Regulation of the Immune Response 0.50 0.02 GNAS,NFKBIE,FGFR4 Th1 and Th2 Activation Pathway 0.50 0.02 APH1A,FGFR4,MAF Endothelin-1 Signaling 0.49 0.02 SHC1,GNAS,FGFR4 Agranulocyte Adhesion and Diapedesis 0.49 0.02 CXCL10,ACTG2,CXCL9 Regulation of the Epithelial-Mesenchymal Transition Pathway 0.49 0.02 PYGO2,APH1A,FGFR4 Ethanol Degradation II 0.49 0.03 ALDH2 Glioma Signaling 0.49 0.02 SHC1,FGFR4 p53 Signaling 0.48 0.02 FGFR4,ATR April Mediated Signaling 0.48 0.03 NFKBIE Notch Signaling 0.48 0.03 APH1A Netrin Signaling 0.47 0.03 PRKAG2 tRNA Charging 0.47 0.03 TARS2 Neuropathic Pain Signaling In Dorsal Horn Neurons 0.47 0.02 FGFR4,PRKAG2 HIF1α Signaling 0.46 0.02 VEGFA,FGFR4 Role of PKR in Interferon Induction and Antiviral Response 0.46 0.03 NFKBIE B Cell Activating Factor Signaling 0.46 0.03 NFKBIE Thyroid Cancer Signaling 0.46 0.03 SHC1 Neuroprotective Role of THOP1 in Alzheimer's Disease 0.46 0.03 PRKAG2 Transcriptional Regulatory Network in Embryonic Stem Cells 0.46 0.03 ONECUT1 Noradrenaline and Adrenaline Degradation 0.46 0.03 ALDH2 IL-8 Signaling 0.46 0.02 VEGFA,GNAS,FGFR4 Rac Signaling 0.45 0.02 PIP5K1A,FGFR4 p38 MAPK Signaling 0.45 0.02 MAPKAPK5,RPS6KA4 MIF Regulation of Innate Immunity 0.45 0.02 NFKBIE Mechanisms of Viral Exit from Host Cells 0.45 0.02 ACTG2 Pancreatic Adenocarcinoma Signaling 0.45 0.02 VEGFA,FGFR4 PTEN Signaling 0.44 0.02 SHC1,FGFR4 UVC-Induced MAPK Signaling 0.44 0.02 ATR Thrombin Signaling 0.44 0.01 SHC1,GNAS,FGFR4 Role of RIG1-like Receptors in Antiviral Innate Immunity 0.43 0.02 NFKBIE Role of Hypercytokinemia/hyperchemokinemia in the Pathogenesis of Influenza 0.43 0.02 CXCL10 Pyrimidine Ribonucleotides Interconversion 0.43 0.02 ENTPD6 Role of p14/p19ARF in Tumor Suppression 0.43 0.02 FGFR4 Natural Killer Cell Signaling 0.43 0.02 SHC1,FGFR4 Role of NANOG in Mammalian Embryonic Stem Cell Pluripotency 0.43 0.02 SHC1,FGFR4 RhoA Signaling 0.43 0.02 PIP5K1A,ACTG2 iNOS Signaling 0.43 0.02 NFKBIE IL-9 Signaling 0.42 0.02 FGFR4 Pyrimidine Ribonucleotides De Novo Biosynthesis 0.42 0.02 ENTPD6 Sperm Motility 0.41 0.02 GNAS,PRKAG2 FXR/RXR Activation 0.41 0.02 PKLR,FGFR4 nNOS Signaling in Neurons 0.40 0.02 CAPN11 GNRH Signaling 0.40 0.02 GNAS,PRKAG2 CCR3 Signaling in Eosinophils 0.39 0.02 GNAS,FGFR4 Gα12/13 Signaling 0.39 0.02 NFKBIE,FGFR4 CD28 Signaling in T Helper Cells 0.39 0.02 NFKBIE,FGFR4 p70S6K Signaling 0.39 0.02 SHC1,FGFR4 PKCθ Signaling in T Lymphocytes 0.39 0.02 NFKBIE,FGFR4 P2Y Purigenic Receptor Signaling Pathway 0.39 0.02 FGFR4,PRKAG2 Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis 0.38 0.01 VEGFA,NFKBIE,FGFR4,CEBPG Adipogenesis pathway 0.38 0.01 FGFR4,SETDB1 Th1 Pathway 0.37 0.01 APH1A,FGFR4 cAMP-mediated signaling 0.37 0.01 GNAS,DRD5,RGS14 CD27 Signaling in Lymphocytes 0.37 0.02 NFKBIE Docosahexaenoic Acid (DHA) Signaling 0.37 0.02 FGFR4 Cardiac β-adrenergic Signaling 0.37 0.01 GNAS,PRKAG2 Systemic Lupus Erythematosus Signaling 0.37 0.01 PRPF3,FGFR4,PRPF40A Phototransduction Pathway 0.36 0.02 PRKAG2 Unfolded protein response 0.36 0.02 CEBPG Aryl Hydrocarbon Receptor Signaling 0.36 0.01 HSP90AB1,ATR D-myo-inositol (1,4,5,6)-Tetrakisphosphate Biosynthesis 0.35 0.01 DUSP11,PTPN12 D-myo-inositol (3,4,5,6)-tetrakisphosphate Biosynthesis 0.35 0.01 DUSP11,PTPN12 Role of CHK Proteins in Cell Cycle Checkpoint Control 0.35 0.02 ATR Melanoma Signaling 0.35 0.02 FGFR4 Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis 0.35 0.01 CTSK,NFKBIE,FGFR4 Human Embryonic Stem Cell Pluripotency 0.35 0.01 GNAS,FGFR4 Regulation of Cellular Mechanics by Calpain Protease 0.34 0.02 CAPN11 IL-12 Signaling and Production in Macrophages 0.34 0.01 FGFR4,MAF Chondroitin Sulfate Biosynthesis 0.33 0.02 B4GALT7 Induction of Apoptosis by HIV1 0.32 0.02 NFKBIE Retinoic acid Mediated Apoptosis Signaling 0.32 0.02 DAP3 Dermatan Sulfate Biosynthesis 0.32 0.02 B4GALT7 ERK5 Signaling 0.31 0.02 RPS6KA4 3-phosphoinositide Degradation 0.31 0.01 DUSP11,PTPN12 Endometrial Cancer Signaling 0.30 0.02 FGFR4 Cell Cycle: G1/S Checkpoint Regulation 0.30 0.02 ATR PXR/RXR Activation 0.30 0.02 PRKAG2 Glioblastoma Multiforme Signaling 0.30 0.01 SHC1,FGFR4 D-myo-inositol-5-phosphate Metabolism 0.30 0.01 DUSP11,PTPN12 Mitotic Roles of Polo-Like Kinase 0.30 0.02 HSP90AB1 UVB-Induced MAPK Signaling 0.30 0.02 FGFR4 Protein Ubiquitination Pathway 0.29 0.01 PSMB4,HSP90AB1,PSMD4 Lymphotoxin β Receptor Signaling 0.29 0.01 FGFR4 GABA Receptor Signaling 0.29 0.01 GNAS IL-10 Signaling 0.29 0.01 NFKBIE Remodeling of Epithelial Adherens Junctions 0.29 0.01 ACTG2 CCR5 Signaling in Macrophages 0.28 0.01 GNAS CXCR4 Signaling 0.28 0.01 GNAS,FGFR4 Glioma Invasiveness Signaling 0.28 0.01 FGFR4 Caveolar-mediated Endocytosis Signaling 0.27 0.01 ACTG2 Melatonin Signaling 0.27 0.01 PRKAG2 Role of MAPK Signaling in the Pathogenesis of Influenza 0.27 0.01 CXCL10 T Helper Cell Differentiation 0.27 0.01 BCL6 Ephrin B Signaling 0.27 0.01 GNAS STAT3 Pathway 0.27 0.01 FGFR4 Serotonin Degradation 0.26 0.01 ALDH2 Germ Cell-Sertoli Cell Junction Signaling 0.26 0.01 FGFR4,ACTG2 Antiproliferative Role of Somatostatin Receptor 2 0.26 0.01 FGFR4 BMP signaling pathway 0.25 0.01 PRKAG2 Non-Small Cell Lung Cancer Signaling 0.25 0.01 FGFR4 Estrogen-Dependent Breast Cancer Signaling 0.25 0.01 FGFR4 Granulocyte Adhesion and Diapedesis 0.25 0.01 CXCL10,CXCL9 Cyclins and Cell Cycle Regulation 0.25 0.01 ATR Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes 0.24 0.01 NFKBIE NF-κB Signaling 0.24 0.01 NFKBIE,FGFR4 ATM Signaling 0.24 0.01 ATR Heparan Sulfate Biosynthesis 0.24 0.01 B4GALT7 Macropinocytosis Signaling 0.24 0.01 FGFR4 Hepatic Fibrosis / Hepatic Stellate Cell Activation 0.24 0.01 VEGFA,CXCL9 Bladder Cancer Signaling 0.22 0.01 VEGFA HER-2 Signaling in Breast Cancer 0.21 0.01 FGFR4 Communication between Innate and Adaptive Immune Cells 0.21 0.01 CXCL10 Crosstalk between Dendritic Cells and Natural Killer Cells 0.21 0.01 ACTG2 OX40 Signaling Pathway 0.21 0.01 NFKBIE FGF Signaling 0.21 0.01 FGFR4 Acute Myeloid Leukemia Signaling 0.21 0.01 FGFR4 Reelin Signaling in Neurons 0.20 0.01 FGFR4 Ceramide Signaling 0.20 0.01 FGFR4 Supplemental table 8: Primer design for CKD susceptibility loci that colocalize with active DREs.

SNP ID Location Gene Forward primer Reversed primer rs2049805 intron GBAP1 CTACACGACGCTCTTCCGATCTAGCAATGAGCAAGTCCCTGATC CAGACGTGTGCTCTTCCGATCATAACTGCCATTAAGCCATT rs267734 non-coding CTACACGACGCTCTTCCGATCTAGTTCAGAAGCGAGCCAAGATC CAGACGTGTGCTCTTCCGATCAGATACCTACTCAGGGGAGC rs11123170 intron PAX8 CTACACGACGCTCTTCCGATCTAGGCCTAACCTACTCAGTGATC CAGACGTGTGCTCTTCCGATCCACCTTTGAATTCCTAAAAGA rs1260326 exon GCKR CTACACGACGCTCTTCCGATCTAGTCCCAATGCAGTCTTTGATC CAGACGTGTGCTCTTCCGATCGTGGGAATACATTCTGGAAA rs13538 exon NAT8 CTACACGACGCTCTTCCGATCTAGCCTCTTCGTTGGCTCAGATC CAGACGTGTGCTCTTCCGATCTTTGGTAAAAAGAGACCCTG rs16853722 intron MECOM CTACACGACGCTCTTCCGATCTAGTAAGGAACTCAAACCGGATC CAGACGTGTGCTCTTCCGATCAGCTGTGTGAATCATAAAGTCA rs13069000 non-coding CTACACGACGCTCTTCCGATCTAGCTTGAGGAATTTGTTTGATC CAGACGTGTGCTCTTCCGATCTCCAGGTTATCATGGCTAAT rs10937329 non-coding CTACACGACGCTCTTCCGATCTAGTACATTTCTGGCTTTGGATC CAGACGTGTGCTCTTCCGATCCACCATTCCTTAAAAACGAG rs347685 intron TFDP2 CTACACGACGCTCTTCCGATCTAGTAAACTGTAGGAAAAAGATC CAGACGTGTGCTCTTCCGATCGATACTGCTGGTTCCTGTGT rs13146355 intron SHROOM3 CTACACGACGCTCTTCCGATCTAGAGCAAAGCGGGCCTAAGATC CAGACGTGTGCTCTTCCGATCTGAATGACTGGTTGATTGAA rs3775948 intron SLC2A9 CTACACGACGCTCTTCCGATCTAGCTTACACATATCATTGGATC CAGACGTGTGCTCTTCCGATCATAGCTGTGTGTATCGGAGC rs2725220 intron PKD2 CTACACGACGCTCTTCCGATCTAGAACAGAACAAAGAGCAGATC CAGACGTGTGCTCTTCCGATCGGAACGAGTTGTAGCAACAT rs17319721 intron SHROOM3 CTACACGACGCTCTTCCGATCTAGTATTCTATCCATTCAAGATC CAGACGTGTGCTCTTCCGATCACCCAGCAGAAATAAAAACA rs11959928 intron DAB2 CTACACGACGCTCTTCCGATCTAGCAAAATCCAAGTTAGAGATC CAGACGTGTGCTCTTCCGATCTAAAGTTGGTTGGCACTTCT rs6420094 intron SLC34A1 CTACACGACGCTCTTCCGATCTAGCTCCTGACCTGCTCAAGATC CAGACGTGTGCTCTTCCGATCTTACAGGTGTGTGCATTCAT rs1936800 non-coding CTACACGACGCTCTTCCGATCTAGTCAAACCATGCTTTAAGATC CAGACGTGTGCTCTTCCGATCTGACAGAAATGAACTGGACA rs9397738 non-coding CTACACGACGCTCTTCCGATCTAGCTCCATTAACATTTTGGATC CAGACGTGTGCTCTTCCGATCACTCCAGTGTAAAAGGGGTT rs881858 non-coding CTACACGACGCTCTTCCGATCTAGGGACATATATGCCAAAGATC CAGACGTGTGCTCTTCCGATCGTCTAAGTCCTGACAGTGGG rs2279463 intron SLC22A2 CTACACGACGCTCTTCCGATCTAGAAGTTTTTATGACTTGGATC CAGACGTGTGCTCTTCCGATCTAAAAATGGCTGGCTGAGTA rs10277115 non-coding CTACACGACGCTCTTCCGATCTAGCTCTGGGACGCTGTGTGATC CAGACGTGTGCTCTTCCGATCATGCACTTCATTTTCAAACA rs6465825 non-coding CTACACGACGCTCTTCCGATCTTAGGTGTGGTAGAATAGATC CAGACGTGTGCTCTTCCGATCGAAGCACTGTAGCAGATTCC rs7805747 intron PRKAG2 CTACACGACGCTCTTCCGATCTCCCAGGAAGACACCGAGATC CAGACGTGTGCTCTTCCGATCTTCTCTGTGCTGCATATCTG rs10109414 non-coding CTACACGACGCTCTTCCGATCTGGATTAGGAAGGGCATGATC CAGACGTGTGCTCTTCCGATCACCTACTGAGCCTAAGGAAAA rs4744712 intron PIP5K1B CTACACGACGCTCTTCCGATCTTTTAAGAGGGACTTACGATC CAGACGTGTGCTCTTCCGATCCTCTCAAAGAAATGCAGAAAA rs10794720 intron WDR37 CTACACGACGCTCTTCCGATCTCCCAGGCTGCCATAAAGATC CAGACGTGTGCTCTTCCGATCGTGCTTTCCTAAGCTTTTTG rs504915 intron NRXN2 CTACACGACGCTCTTCCGATCTGCAGCCTTGCTCTCAGGATC CAGACGTGTGCTCTTCCGATCTAGGAGAGAGCTTTCCTTGG rs10774021 intron SLC6A13 CTACACGACGCTCTTCCGATCTTTTGGAACATAGCAGAGATC CAGACGTGTGCTCTTCCGATCACCTCGTCTTCCTCTTTACC rs653178 intron ATXN2 CTACACGACGCTCTTCCGATCTTCAAGTCTCTCCCAACGATC CAGACGTGTGCTCTTCCGATCTCCTCAGCCATACTAATCGT rs626277 intron DACH1 CTACACGACGCTCTTCCGATCTGCTTATTTGAAGTTATGATC CAGACGTGTGCTCTTCCGATCTTAAATCATTTTGCGATTGT rs2453533 non-coding CTACACGACGCTCTTCCGATCTCCAGCAATGATTATCTGATC CAGACGTGTGCTCTTCCGATCTCCAAACCATACCTAAGGAG rs17730281 exon WDR72 CTACACGACGCTCTTCCGATCTCTCTGCTGTTTGATGAGATC CAGACGTGTGCTCTTCCGATCTGACAAAATTCTAGCAGGAAA rs17730436 intron WDR72 CTACACGACGCTCTTCCGATCTGGTAGTCTACAAGCTTGATC CAGACGTGTGCTCTTCCGATCACGCAGAGTTGAGTAGGTGT rs889472 non-coding CTACACGACGCTCTTCCGATCTACAGTGTGAATCCTTAGATC CAGACGTGTGCTCTTCCGATCCATGCCTGGATTTACATCTT rs11868441 intron BCAS3 CTACACGACGCTCTTCCGATCTTGGGACGACTACAAGAGATC CAGACGTGTGCTCTTCCGATCGGCCCTAGTAAATGGAAAAT rs9895661 intron BCAS3 CTACACGACGCTCTTCCGATCTTCCCTTCCCACTGGAGGATC CAGACGTGTGCTCTTCCGATCTACCTCTCCTCCTTCGTGTA rs7227483 intron SLC14A2 CTACACGACGCTCTTCCGATCTAGTGGCTCTTATGGTAGATC CAGACGTGTGCTCTTCCGATCTGCAAGGAATGCTAAGAAAT rs12460876 intron SLC7A9 CTACACGACGCTCTTCCGATCTAAAAGCGTTTTGGCTAGATC CAGACGTGTGCTCTTCCGATCACCAGATGGGTCTAAAGGAT rs6026584 intron GNAS CTACACGACGCTCTTCCGATCTACGTAATATTTAGCAGGATC CAGACGTGTGCTCTTCCGATCATGGAGGCATGTGTTTCTAC rs911119 intron CST3 CTACACGACGCTCTTCCGATCTCCAGATTTAGGACTGAGATC CAGACGTGTGCTCTTCCGATCGGTCAGGGATATTTCCAAGT SIGNIFICANCE STATEMENT

Genome-wide association studies (GWASs) have identified a number of genetic regions correlated with development of CKD, but establishing causal- ity remains challenging. This study applies a new approach to GWAS interpretation: to complement classic annotation on the basis of linear spatial prox- imity, the principle of transcriptional dysregulation is used to identify sites where CKD-associated variation colocalizes with DNA regulatory elements. The study describes the identification of 304 candidate genes that physically interact with regulatory elements that colocalize with 39 common variants associated with CKD. Future studies will be required to verify the findings of this screening pipeline, but the method could help to determine the causal roles that common variants play in complex diseases, such as CKD.