title: Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
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<10(-16)). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes.
authors.affiliation: Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.forename: Danny
authors.initials: D
authors.lastname: Arends
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Asia
authors.initials: A
authors.lastname: Smolonska
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.forename: Sander
authors.initials: S
authors.lastname: Rensen
authors.forename: Marcel G M
authors.initials: MG
authors.lastname: Wolfs
authors.forename: Mathieu
authors.initials: M
authors.lastname: Platteel
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Clara C
authors.initials: CC
authors.lastname: Elbers
authors.forename: Eleanora M
authors.initials: EM
authors.lastname: Festen
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Christiaan G J
authors.initials: CG
authors.lastname: Saris
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Te Meerman
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D006680:HLA Antigens