TY - JOUR
T1 - Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression
AU - CommonMind Consortium
AU - Hauberg, Mads Engel
AU - Zhang, Wen
AU - Giambartolomei, Claudia
AU - Franzén, Oscar
AU - Morris, David L.
AU - Vyse, Timothy J.
AU - Ruusalepp, Arno
AU - Fromer, Menachem
AU - Sieberts, Solveig K.
AU - Johnson, Jessica S.
AU - Ruderfer, Douglas M.
AU - Shah, Hardik R.
AU - Klei, Lambertus L.
AU - Dang, Kristen K.
AU - Perumal, Thanneer M.
AU - Logsdon, Benjamin A.
AU - Mahajan, Milind C.
AU - Mangravite, Lara M.
AU - Essioux, Laurent
AU - Toyoshiba, Hiroyoshi
AU - Gur, Raquel E.
AU - Hahn, Chang Gyu
AU - Lewis, David A.
AU - Haroutunian, Vahram
AU - Peters, Mette A.
AU - Lipska, Barbara K.
AU - Buxbaum, Joseph D.
AU - Hirai, Keisuke
AU - Domenici, Enrico
AU - Devlin, Bernie
AU - Sklar, Pamela
AU - Schadt, Eric E.
AU - Björkegren, Johan L.M.
AU - Roussos, Panos
N1 - Publisher Copyright:
© 2017
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - GWASs
KW - Mendelian randomization
KW - antagonistic pleiotropy
KW - common genetic variation
KW - complex diseases
KW - complex traits
KW - cross phenotype
KW - eQTLs
KW - expression quantitative trait loci
KW - gene expression
KW - gene-set enrichment analysis
KW - genome-wide association studies
UR - http://www.scopus.com/inward/record.url?scp=85019924188&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2017.04.016
DO - 10.1016/j.ajhg.2017.04.016
M3 - Article
C2 - 28552197
AN - SCOPUS:85019924188
SN - 0002-9297
VL - 100
SP - 885
EP - 894
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -