Detection and replication of epistasis influencing transcription in humans

Hemani, Gibran, Shakhbazov, Konstantin, Westra, Harm-Jan, Esko, Tonu, Henders, Anjali K., McRae, Allan F., Yang, Jian, Gibson, Greg, Martin, Nicholas G., Metspalu, Andres, Franke, Lude, Montgomery, Grant W., Visscher, Peter M. and Powell, Joseph E. (2014) Detection and replication of epistasis influencing transcription in humans. Nature, 508 7495: 249-253. doi:10.1038/nature13005

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Author Hemani, Gibran
Shakhbazov, Konstantin
Westra, Harm-Jan
Esko, Tonu
Henders, Anjali K.
McRae, Allan F.
Yang, Jian
Gibson, Greg
Martin, Nicholas G.
Metspalu, Andres
Franke, Lude
Montgomery, Grant W.
Visscher, Peter M.
Powell, Joseph E.
Title Detection and replication of epistasis influencing transcription in humans
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
1476-4687
Publication date 2014-02-26
Year available 2014
Sub-type Article (original research)
DOI 10.1038/nature13005
Open Access Status File (Author Post-print)
Volume 508
Issue 7495
Start page 249
End page 253
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
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(1) and contributes to their variation(2,3) is a fundamental question in evolution andhuman genetics. Although oftendemonstrated 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 among natural polymorphisms in human traits(7,8). Its absence from empirical findingsmay 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 owing to statistical and computational issues(9). Here we show, using advanced computation(10) and a gene expression study design, that many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individualswith 7,339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between commonSNPs influencing the expression of 238 genes (P < 2.91 x 10(-16)). Replication of these interactions in two independent data sets11,12 showed both concordance of direction of epistatic effects (P = 55.5 x 10(-31)) and enrichment of interaction P values, with 30 being significant at a conservative threshold of P < 9.98 x 10(-5). Forty-four of the genetic interactions are located within 5 megabases of regions of known physical chromosome interactions(13) (P=1.8x10(-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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 389892
DE130100691
GM057091
389892
AA07535
BSIK03009
918.66.620
MLDS WO11-30
92519031
259867
SF0180142s08
SP1GVARENG
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
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