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Shared Genetic Architecture and Casual Relationship Between Leptin Epidemiology/Health Services Research BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2019-001140 on 26 April 2020. Downloaded from Open access Original research Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large- scale cross- trait meta-analysis and Mendelian randomization analysis Xinpei Wang ,1 Jinzhu Jia,1,2 Tao Huang3,4 To cite: Wang X, Jia J, ABSTRACT Huang T. Shared genetic Objective We aimed to estimate genetic correlation, Significance of this study architecture and casual identify shared loci and test causality between leptin levels relationship between leptin and type 2 diabetes (T2D). What is already known about this subject? levels and type 2 diabetes: Research design and methods Our study consists of ► Both leptin levels and type 2 diabetes (T2D) are large- scale cross- trait meta- strongly associated with glycemic homeostasis. analysis and Mendelian three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage ► Previous observational and genetic studies have randomization analysis. found a strong association between leptin levels and disequilibrium score regression analysis. Second, we BMJ Open Diab Res Care T2D. 2020;8:e001140. doi:10.1136/ conducted a large- scale genome- wide cross- trait meta- bmjdrc-2019-001140 analysis using cross-phenotype association to identify ► However, the exact mechanism of the association shared loci between trait pairs that showed significant remains unclear. genetic correlations in the first part. In the end, we carried What are the new findings? ► Additional material is out a bidirectional MR analysis to find out whether there ► We identified several previously unreported genetic published online only. To view is a causal relationship between leptin levels and T2D or please visit the journal online loci that influence both leptin levels and T2D or gly- glycemic traits. (http:// dx. doi. org/ 10. 1136/ cemic traits. Results We found positive genetic correlations between bmjdrc- 2019- 001140). ► Our MR analysis found a causal relationship between leptin levels and T2D (R =0.3165, p=0.0227), fasting g homeostasis model assessment- insulin resistance insulin (FI) (R =0.517, p=0.0076), homeostasis model g and leptin levels, suggesting that the association be- Received 18 December 2019 assessment- insulin resistance (HOMA- IR) (R =0.4785, g tween leptin levels and T2D or glycemic traits may Revised 3 March 2020 p=0.0196), as well as surrogate estimates of β-cell be due to both the common genetic architecture and http://drc.bmj.com/ Accepted 12 March 2020 function (HOMA-β) (R =0.4456, p=0.0214). We identified g causal effect. 12 shared loci between leptin levels and T2D, 1 locus A series of post-genome wide association studies between leptin levels and FI, 1 locus between leptin levels ► functional analysis provided biologic insights into and HOMA- IR, and 1 locus between leptin levels and HOMA- . We newly identified eight loci that did not achieve the shared genes between leptin levels and T2D or © Author(s) (or their β genome- wide significance in trait- specific genome- wide glycemic traits and found the tissues and biologic employer(s)) 2020. Re- use processes in which these shared genes were signifi- permitted under CC BY- NC. No association studies. These shared genes were enriched cantly expressed. on September 23, 2021 by guest. Protected copyright. commercial re- use. See rights in pancreas, thyroid gland, skeletal muscle, placenta, and permissions. Published liver and cerebral cortex. In addition, we found that 1-SD ► Transcriptome- wide association analysis (TWAS) by BMJ. increase in HOMA- IR was causally associated with a 0.329 further assessed the association of gene expression 1Department of Biostatistics, ng/mL increase in leptin levels (β=0.329, p=0.001). in specific tissue between leptin levels and T2D or School of Public Health, Peking Conclusions Our results have shown the shared genetic glycemic traits and found the gene–tissue pair that University, Beijing, China architecture between leptin levels and T2D and found was overlapped between TWAS for both leptin levels 2 Center for Statistical Science, causality of HOMA- IR on leptin levels, shedding light on the and T2D or glycemic traits. Peking University, Beijing, China 3 molecular mechanisms underlying the association between Department of Epidemiology & leptin levels and T2D. Biostatistics, School of Public Previous convincing observational studies Health, Peking University, have reported that there was a positive asso- Beijing, China 4–6 4Department of Global Health, INTRODUCTION ciation between leptin levels and T2D. School of Public Health, Peking Type 2 diabetes (T2D) is a complex and More persuasive meta-analyses showed University, Beijing, China serious global disease,1 which reduces life similar results. Interestingly,7–9 genome- wide expectancy of patients and imposes huge association studies (GWAS) have reported Correspondence to Dr Jinzhu Jia; jzjia@ pku. edu. cn economic burdens on patients as well as the some single nucleotide polymorphisms 2 3 and Dr Tao Huang; whole society. However, its etiology is not (SNPs) have effects on both leptin levels and huangtaotao@ pku. edu. cn fully understood. T2D,10–12 leading us to wonder whether the BMJ Open Diab Res Care 2020;8:e001140. doi:10.1136/bmjdrc-2019-001140 1 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2019-001140 on 26 April 2020. Downloaded from Epidemiology/Health Services Research (12 171 cases and 56 862 controls), the Asian Genetic How might these results change the focus of research or Epidemiology Network Type 2 Diabetes (AGEN-T2D) clinical practice? Consortium (6952 cases and 11 865 controls), the South Asian Type 2 Diabetes (SAT2D) Consortium (5561 cases ► Our results further elucidate the specific mechanism of the asso- ciation between leptin levels and T2D or glycemic traits, suggest- and 14 458 controls) and the Mexican American Type ing that the association between leptin levels and T2D or glycemic 2 Diabetes (MAT2D) Consortium (1804 cases and 779 14 traits may be due to both the common genetic architecture and controls). The GWAS summary statistics for FG, FI, causal effect. HOMA- IR and HOMA-β were from the Meta-Analyses ► The discovery of shared genes provided new predictors for identifi- of Glucose and Insulin-related traits Consortium.12 This cation of susceptible people. meta- analysis included up to 46 186 non-diabetic partic- ► The results of tissue analysis suggested that clinical workers should ipants of European descent informative for FG, and up pay more attention to the complications of these tissues in T2D to 38 238 non- diabetic individuals informative for FI, as patients with abnormal leptin levels. well as HOMA-β and HOMA- IR. More detailed informa- tion about these researches can be seen in the original publications.12–14 association between leptin levels and T2D is due to a common genetic etiology. Besides, leptin levels and T2D Statistical analysis may also have common risk factors that are controlled LD score regression analysis by same genes or pathways. However, no genetic study LDSC was used to compute the genetic correlation has explored the common genetic architecture between between leptin levels and T2D or glycemic traits in our leptin levels and T2D. genome- wide genetic correlation analysis.15 This method Therefore, we conducted this large-scale genome-wide believes that the GWAS effect size estimate for a given cross-trait meta-analysis among 254 263 participants to SNP is related to the effects of all SNPs in LD with that identify shared genetic architecture between leptin levels SNP. Thus, SNPs with higher LD scores will have higher and T2D or glycemic traits, providing more knowledge test statistics as well. about shared molecular mechanism of them. Further- more, we explored the potential causality between leptin Partitioned genetic correlation 16 levels with T2D or glycemic traits by using bidirectional By using partitioned LDSC, we further estimated the Mendelian randomization (MR) analysis. partitioned genetic correlation between leptin levels and T2D or glycemic traits in 11 functional categories, including DNase I digital genomic foot printing region, RESEARCH DESIGN AND METHODS DNase I hypersensitivity sites (DHSs), fetal DHS, intron, Study design super- enhancer, transcription factor-binding sites, tran- To identify the shared genetic architecture between scribed regions and histone marks H3K4me1, H3K27ac, leptin levels and T2D or glycemic traits, we conducted H3K4me3 and H3K9ac. This method partitions SNPs a large-scale genome-wide cross-trait meta-analysis. Our into different functional categories and calculates LD http://drc.bmj.com/ study consists of three parts. First, we calculated the score for a given SNP to that category. genetic correlation of leptin levels and T2D or glycemic traits, including fasting glucose (FG), fasting insulin Cross-trait meta-analysis (FI), insulin resistance derived from fasting variables by We conducted a genome-wide cross- trait meta- analysis homeostasis model assessment (HOMA-IR) and surro- to identify shared loci between leptin levels and T2D or 17 gate estimates of β-cell function (HOMA-β) by using glycemic traits using CPASSOC. This method can inte- on September 23, 2021 by guest. Protected copyright. linkage disequilibrium (LD) score regression analysis grate association evidence from summary statistics of (LDSC). Second,
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