학술논문
Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
Document Type
article
Author
Fehrmann, Rudolf SN; Jansen, Ritsert C; Veldink, Jan H; Westra, Harm-Jan; Arends, Danny; Bonder, Marc Jan; Fu, Jingyuan; Deelen, Patrick; Groen, Harry JM; Smolonska, Asia; Weersma, Rinse K; Hofstra, Robert MW; Buurman, Wim A; Rensen, Sander; Wolfs, Marcel GM; Platteel, Mathieu; Zhernakova, Alexandra; Elbers, Clara C; Festen, Eleanora M; Trynka, Gosia; Hofker, Marten H; Saris, Christiaan GJ; Ophoff, Roel A; van den Berg, Leonard H; van Heel, David A; Wijmenga, Cisca; Te Meerman, Gerard J; Franke, Lude
Source
PLoS genetics. 7(8)
Subject
Language
Abstract
For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P