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Am J Hum Genet. 2017 Jun 1;100(6):885-894. doi: 10.1016/j.ajhg.2017.04.016. Epub 2017 May 25.

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression.

Author information

1
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lundbeck Foundation Initiative of Integrative Psychiatric Research, Aarhus University, Aarhus 8000, Denmark; Centre for Integrative Sequencing, Aarhus University, Aarhus 8000, Denmark. Electronic address: hauberg@biomed.au.dk.
2
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Department of Genetics and Genomic Sciences and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
5
Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK; Division of Immunology, Infection, and Inflammatory Disease, King's College London, London SE1 1UL, UK.
6
Clinical Gene Networks AB, Stockholm 114 44, Sweden; Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu 50411, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu 50411, Estonia.
7
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Department of Genetics and Genomic Sciences and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Clinical Gene Networks AB, Stockholm 114 44, Sweden; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu 50411, Estonia.
9
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, New York, NY 10468, USA. Electronic address: panagiotis.roussos@mssm.edu.

Abstract

Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate < 0.05. These genes were often not closest to the genetic variant and were primarily identified in eQTLs derived from pathophysiologically relevant tissues. For instance, genes with expression changes associated with lipid traits were mostly identified in the liver, and those associated with cardiovascular disease were identified in arterial tissue. The affected genes additionally point to biological processes implicated in the interrogated traits, such as the interleukin-27 pathway in rheumatoid arthritis. Further, comparing trait-associated gene expression changes across traits suggests that pleiotropy is a widespread phenomenon and points to specific instances of both agonistic and antagonistic pleiotropy. For instance, expression of SNX19 and ABCB9 is positively correlated with both the risk of schizophrenia and educational attainment. To facilitate interpretation, we provide this lexicon of how common trait-associated genetic variants alter gene expression in various tissues as the online database GWAS2Genes.

KEYWORDS:

GWASs; Mendelian randomization; antagonistic pleiotropy; common genetic variation; complex diseases; complex traits; cross phenotype; eQTLs; expression quantitative trait loci; gene expression; gene-set enrichment analysis; genome-wide association studies

PMID:
28552197
PMCID:
PMC5474225
DOI:
10.1016/j.ajhg.2017.04.016
[Indexed for MEDLINE]
Free PMC Article

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