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; Jinzhu Jia; Tao Huang

doi:10.1136/bmjdrc-2019-001140

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

BMJ Open Diabetes Res Care. 2020 Apr;8(1):e001140. doi: 10.1136/bmjdrc-2019-001140.

Authors

Xinpei Wang¹, Jinzhu Jia^{2

3}, Tao Huang^{4

5}

Affiliations

¹ Department of Biostatistics, School of Public Health, Peking University, Beijing, China.
² Department of Biostatistics, School of Public Health, Peking University, Beijing, China jzjia@pku.edu.cn huangtaotao@pku.edu.cn.
³ Center for Statistical Science, Peking University, Beijing, China.
⁴ Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China jzjia@pku.edu.cn huangtaotao@pku.edu.cn.
⁵ Department of Global Health, School of Public Health, Peking University, Beijing, China.

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 (R_g=0.3165, p=0.0227), fasting insulin (FI) (R_g=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (R_g=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (R_g=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-β. 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 (β=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.

Keywords: genetic association; genetic epidemiology; leptin; type 2 diabetes.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / genetics
Female
Genome-Wide Association Study
Humans
Leptin / genetics
Mendelian Randomization Analysis*
Phenotype
Pregnancy

Substances

Leptin