title: Detection and replication of epistasis influencing transcription in humans.
abstract: Epistasis is the phenomenon whereby one polymorphism's effect on a trait depends on other polymorphisms present in the genome. The extent to which epistasis influences complex traits and contributes to their variation is a fundamental question in evolution and human genetics. Although often demonstrated in artificial gene manipulation studies in model organisms, and some examples have been reported in other species, few examples exist for epistasis among natural polymorphisms in human traits. Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits, but an alternative view is that it has previously been too technically challenging to detect owing to statistical and computational issues. Here we show, using advanced computation and a gene expression study design, that many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7,339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between common SNPs influencing the expression of 238 genes (P < 2.91 × 10(-16)). Replication of these interactions in two independent data sets showed both concordance of direction of epistatic effects (P = 5.56 × 10(-31)) and enrichment of interaction P values, with 30 being significant at a conservative threshold of P < 9.98 × 10(-5). Forty-four of the genetic interactions are located within 5 megabases of regions of known physical chromosome interactions (P = 1.8 × 10(-10)). Epistatic networks of three SNPs or more influence the expression levels of 129 genes, whereby one cis-acting SNP is modulated by several trans-acting SNPs. For example, MBNL1 is influenced by an additive effect at rs13069559, which itself is masked by trans-SNPs on 14 different chromosomes, with nearly identical genotype-phenotype maps for each cis-trans interaction. This study presents the first evidence, to our knowledge, for many instances of segregating common polymorphisms interacting to influence human traits.
authors.affiliation: 1] Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.affiliation: 1] Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shakhbazov
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia [2] Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [3] Divisions of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Tonu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: 1] Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Biology and Centre for Integrative Genomics, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: 1] Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia [2].
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: 1] Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia [3].
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: 1] Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia [3].
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
mesh_terms: D015331:Cohort Studies; D004843:Epistasis, Genetic / Q000235:genetics*; D005060:Europe / Q000208:ethnology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D014158:Transcription, Genetic / Q000235:genetics*