Detection and replication of epistasis influencing transcription in humans

Gibran Hemani, Konstantin Shakhbazov, Harm-Jan Westra, Tonu Esko, Anjali K. Henders, Allan F. McRae, Jian Yang, Greg Gibson, Nicholas G. Martin, Andres Metspalu, Lude Franke, Grant W. Montgomery (+2 others)
2014 Nature  
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 1 and contributes to their variation 2,3 is a fundamental question in evolution and human genetics. Though often demonstrated in artificial gene manipulation studies in model organisms 4, 5 , and some examples have been reported in other species 6 , few examples exist for epistasis amongst natural polymorphisms in
more » ... uman traits 7, 8 . Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits 2,3 , but an alternative view is that it has previously been too technically challenging to detect due to statistical and computational issues 9 . Here we show that, using advanced computation 10 and a gene expression study design, many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7339 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 11, 12 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 < 0.05/501. Fortyfour of the genetic interactions are located within 2Mb of regions of known physical chromosome interactions 13 (p = 1.8 × 10 −10 ). Epistatic networks of three SNPs or more influence the expression Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
doi:10.1038/nature13005 pmid:24572353 pmcid:PMC3984375 fatcat:eyw2j6n23zbeblqjn4vgiud4vu