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Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis.

ABSTRACT: OBJECTIVE:We aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS:Our study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits. RESULTS:We found positive genetic correlations between leptin levels and T2D (Rg=0.3165, p=0.0227), fasting insulin (FI) (Rg=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (Rg=0.4785, p=0.0196), as well as surrogate estimates of ?-cell function (HOMA-?) (Rg=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-?. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (?=0.329, p=0.001). CONCLUSIONS:Our results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

SUBMITTER: Wang X

PROVIDER: S-EPMC7202746 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis.

Wang Xinpei X Jia Jinzhu J Huang Tao T

BMJ open diabetes research & care 20200401 1

<h4>Objective</h4>We aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).<h4>Research design and methods</h4>Our study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci be ...[more]

PMID: 32341051

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Dataset Information

Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis.

Publications

Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis.

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