Multi‐tissue transcriptome‐wide association study reveals susceptibility genes and drug targets for insulin resistance‐relevant phenotypes

Author:

Duan Yuan‐Yuan1,Ke Xin1,Wu Hao1,Yao Shi1,Shi Wei1,Han Ji‐Zhou1,Zhu Ren‐Jie1,Wang Jia‐Hao1,Jia Ying‐Ying1,Yang Tie‐Lin1,Li Meng2,Guo Yan1ORCID

Affiliation:

1. Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technology Xi'an Jiaotong University Xi'an China

2. Department of Orthopedics The First Affiliated Hospital of Xi'an Jiaotong University Xi'an China

Abstract

AbstractAimGenome‐wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)‐relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR‐relevant phenotypes via a transcriptome‐wide association study.Materials and MethodsWe conducted a large‐scale multi‐tissue transcriptome‐wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment‐IR, fasting insulin) and lipid‐relevant traits (high‐density lipoprotein cholesterol, triglycerides, low‐density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis.ResultsWe identified 1190 susceptibility genes causally associated with IR‐relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR‐related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR‐related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk.ConclusionsOur study provided new insights into IR aetiology and avenues for therapeutic development.

Funder

Fundamental Research Funds for the Central Universities

National Natural Science Foundation of China

Publisher

Wiley

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3