@article{68c70de8c3974ed7b95d1eff40599a1e,
title = "Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits",
abstract = "Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.",
keywords = "GWAS, adipocyte, colocalization, diabetes, eQTL, lipid, obesity, secondary signal, trans-ancestry, waist-hip ratio",
author = "Raulerson, {Chelsea K.} and Arthur Ko and Kidd, {John C.} and Currin, {Kevin W.} and Brotman, {Sarah M.} and Cannon, {Maren E.} and Ying Wu and Spracklen, {Cassandra N.} and Jackson, {Anne U.} and Stringham, {Heather M.} and Welch, {Ryan P.} and Christian Fuchsberger and Locke, {Adam E.} and Narisu Narisu and Lusis, {Aldons J.} and Mete Civelek and Furey, {Terrence S.} and Johanna Kuusisto and Collins, {Francis S.} and Michael Boehnke and Scott, {Laura J.} and Lin, {Dan Yu} and Love, {Michael I.} and Markku Laakso and P{\"a}ivi Pajukanta and Mohlke, {Karen L.}",
note = "Funding Information: The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 02/23/17 and dbGaP accession number phs000424.v7.p2 on 08/22/17. Funding Information: This study was supported by NIH grants R01DK093757, R01DK072193, U01DK105561, U01DK062370, 1-ZIA-HG000024, P01HL28481, R01HG009937, R01MH118349, P01CA142538, and P30ES010126; the Academy of Finland; the Finnish Heart Foundation; the Finnish Diabetes Foundation; Finnish Funding Agency for Technology and Innovation (TEKES) contract 1510/31/06; and the Commission of the European Community HEALTH-F2-2007-201681. Individuals were supported by NIH: T32GM067553 (C.K.R. K.W.C.), F31HL127921 (A.K.), T32GM007092 (S.M.B.), and R25GM055336 (K.W.C.). C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. We thank the UCLA Neuroscience Genomics Core (UNGC) for generation of RNA-sequencing data, Peter Chines for his contributions to METSIM genotyping, and Karl Eklund for his assistance with read-level quality control. We also thank the Roadmap Epigenomics Project for their adipose nuclei promoter and enhancer marks. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 02/23/17 and dbGaP accession number phs000424.v7.p2 on 08/22/17. Funding Information: This study was supported by NIH grants R01DK093757 , R01DK072193 , U01DK105561 , U01DK062370 , 1-ZIA-HG000024 , P01HL28481 , R01HG009937 , R01MH118349 , P01CA142538 , and P30ES010126 ; the Academy of Finland ; the Finnish Heart Foundation ; the Finnish Diabetes Foundation ; Finnish Funding Agency for Technology and Innovation (TEKES) contract 1510/31/06 ; and the Commission of the European Community HEALTH-F2-2007-201681 . Individuals were supported by NIH: T32GM067553 (C.K.R., K.W.C.), F31HL127921 (A.K.), T32GM007092 (S.M.B.), and R25GM055336 (K.W.C.). C.N.S. was supported by the American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016 . Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",
year = "2019",
month = oct,
day = "3",
doi = "10.1016/j.ajhg.2019.09.001",
language = "English",
volume = "105",
pages = "773--787",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
number = "4",
}