Cross-ancestry genome-wide association study and systems-level integrative analyses implicate new risk genes and therapeutic targets for depression

Author:

Li Yifan,Dang Xinglun,Chen Rui,Wang Junyang,Li Shiwu,Mitchell Brittany L.,Yao Yong-GangORCID,Li Ming,Li Tao,Zhang Zhijun,Luo Xiong-Jian

Abstract

AbstractDeciphering the genetic architecture of depression is pivotal for characterizing the associated pathophysiological processes and development of new therapeutics. Here we conducted a cross-ancestry genome-wide meta-analysis on depression (416,437 cases and 1,308,758 controls) and identified 287 risk loci, of which 140 are new. Variant-level fine-mapping prioritized potential causal variants and functional genomic analysis identified variants that regulate the binding of transcription factors. We validated that 80% of the identified functional variants are regulatory variants and expression quantitative trait loci (eQTL) analysis uncovered the potential target genes regulated by the prioritized risk variants. Gene-level analysis, including transcriptome-wide association study (TWAS), proteome-wide association study (PWAS), colocalization and Mendelian randomization-based analyses, prioritized potential causal genes and drug targets. Combining evidence from different analyses revealed likely causal genes, includingTMEM106B, CTNND1, EPHB2, AREL1, CSE1L, RAB27B, SATU1, TMEM258, DCC, etc. Pathway analysis showed significant enrichment of depression risk genes in synapse-related pathways. Finally, we showed thatTmem106bknockdown resulted in depression-like behaviors in mice, supporting involvement ofTmem106bin depression. Our study identified new risk loci, likely causal variants and genes for depression, providing important insights into the genetic architecture of depression and potential therapeutic targets.

Publisher

Cold Spring Harbor Laboratory

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