Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Abstract

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes. Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

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Affiliated Institutions

• Universitätsmedizin Greifswald DE
• Radboud Institute for Molecular Life Sciences NL
• Tampere University Hospital FI
• Agency for Science, Technology and Research SG
• Maastricht University NL
• University of Exeter GB
• Helmholtz Zentrum München DE
• University of Groningen NL
• Amsterdam University Medical Centers NL
• Garvan Institute of Medical Research AU
• IFB Adiposity Diseases DE
• Leipzig University DE
• Karolinska Institutet SE
• The University of Queensland AU
• Utrecht University NL
• Centre for Human Genetics GB
• Institute for Molecular Medicine Finland FI
• Ontario Institute for Cancer Research CA
• University of Oulu FI
• Singapore Immunology Network SG
• Finnish Institute for Health and Welfare FI
• Amsterdam Neuroscience NL
• University of Helsinki FI
• University Medical Center Utrecht NL
• Vrije Universiteit Amsterdam NL
• Fimlab (Finland) FI
• SIB Swiss Institute of Bioinformatics CH
• University of Liège BE
• University of Cambridge GB
• European Molecular Biology Laboratory DE
• Leiden University Medical Center NL
• University of Geneva CH
• University of Oxford GB
• University of Turku FI
• University Medical Center Groningen NL
• Erasmus MC NL
• Tampere University FI
• University of Bristol GB
• Leipzig Heart Institute DE
• Royal Devon and Exeter Hospital GB
• University of Chicago US
• Oncode Institute NL
• Walloon Excellence in Lifesciences and Biotechnology BE
• Stanford University US
• Georgia Institute of Technology US
• Johns Hopkins University US
• University of Tartu EE
• University of Washington US
• Radboud University Medical Center NL
• Chicago Department of Public Health US
• University of Tasmania AU
• German Centre for Cardiovascular Research DE
• University of Lausanne CH
• Radboud University Nijmegen NL

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