Epistasis is widespread in the genetic control of transcription in humans. J. Powell1,2, G. Hemani1,2, K. Shakhbazov1,2, A. Henders3, A. McRae1,2, N. Martin3, G. Montgomery3, P. Visscher1,2 1) Complex Trait Genomics, The University of Queensland Diamantina Institute, Brisbane, Qld, Australia; 2) Complex Trait Genomics, Queensland Brain Institute, University of Queensland, Brisbane, Qld, Australia; 3) The Queensland Institute of Medical Research, Brisbane, Qld, Australia.
A long standing question in evolution and genetics is the extent to which epistasis, the phenomenon whereby one polymorphism's effect on a trait depends on other polymorphisms present in the genome, contributes to complex trait variation. Though epistasis has been demonstrated in artificial gene manipulation studies in model organisms, and some examples have been shown in other species, few convincing examples exist for variation due to epistasis among natural polymorphisms in human traits. Its absence from empirical findings may simply be due to its unimportance in the genetic variation for complex traits, but we hypothesized that it has previously been too technically difficult to detect for pairs of loci due to statistical power and computational issues. Here we show that, using advanced computation techniques and a gene expression study design, evidence for abundant pairwise epistatic loci is found. In a cohort of 842 individuals with data on 7339 gene expression levels in whole blood, we found that after stringent correction for multiple testing the expression of 249 genes is influenced by 549 significant pairwise epistatic interactions. We attempted replication in two independent datasets and 421 show evidence of significance in at least one dataset. We provide evidence of functional enrichment for the interacting SNPs, for instance 49 of the genetic interactions are located within 500kb of known chromosome interactions (p < 1.1*10-70). 129 genes are controlled by multi-locus epistatic interactions whereby one cis-acting single nucleotide polymorphism (SNP) is modulated by several trans-acting SNPs. For example, a gene on chromosome 3 is controlled by a cis-additive effect which itself is controlled by trans-SNPs on 18 different chromosomes, with nearly identical genotype-phenotype maps for each cis-trans interaction. This study presents the first strong evidence for the widespread existence of epistasis effects on trait variance emerging from natural genetic variation in humans.
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