We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40–80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.
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We thank the DIAGRAM, MAGIC, GIANT, GLGC, CARDIoGRAM, ICBP, IGAP, and IIBDGC consortia for making their GWAS meta-analysis summary statistics publicly available. This work was conducted using the UK Biobank Resource (application number 25331). E.R.G. acknowledges support from R01-MH101820, R01-MH090937, R01-MH113362, and R01-CA157823 and benefited immensely from a Fellowship at Clare Hall, University of Cambridge. A.V.S., F.A., M.K., G.G., and K.G.A. acknowledge support from the NIH contract HHSN268201000029C to The Broad Institute, Inc. M.v.d.B. acknowledges support by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. F.H. and E.E. are supported by NIH grants R01-MH101782 and R01-ES022282. X.W. acknowledges support from NIH grants R01-HG007022 and R01-AR042742. M.I.McC. is a Wellcome Senior Investigator supported by Wellcome (098381, 090532, 106130, 203141) and the NIH (U01-DK105535, R01-MH101814). E.T.D. acknowledges support from the Swiss National Science Foundation, the European Research Council, the NIH-NIMH, and the Louis Jeantet Foundation. N.J.C. is supported by R01-MH113362, R01-MH101820, and R01-MH090937. The datasets used for part of the replication analysis were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10-RR025141, and CTSA grants UL1-TR002243, UL1-TR000445, and UL1-RR024975. Genomic data are also supported by investigator-led projects that include U01-HG004798, R01-NS032830, RC2-GM092618, P50-GM115305, U01-HG006378, U19-HL065962, and R01-HD074711, and additional funding sources listed at https://victr.vanderbilt.edu/pub/biovu/.
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