Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
QIMR Home Page
GenEpi Home Page
Publications
Contacts
Research
Staff Index
Collaborators
Software Tools
Computing Resources
Studies
Search
GenEpi Intranet
PMID
24572353
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.
DATE PUBLISHED
2014 Apr 10
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2013/09/20
accepted 2014/01/07
aheadofprint 2014/02/26
entrez 2014/02/28 06:00
pubmed 2014/02/28 06:00
medline 2014/05/16 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Hemani G Hemani Gibran G 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.
Shakhbazov K Shakhbazov Konstantin K 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.
Westra HJ Westra Harm-Jan HJ Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Esko T Esko Tonu T 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.
Henders AK Henders Anjali K AK Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
McRae AF McRae Allan F AF 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.
Yang J Yang Jian J Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.
Gibson G Gibson Greg G School of Biology and Centre for Integrative Genomics, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
Martin NG Martin Nicholas G NG Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
Metspalu A Metspalu Andres A Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
Franke L Franke Lude L Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Montgomery GW Montgomery Grant W GW 1] Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia [2].
Visscher PM Visscher Peter M PM 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].
Powell JE Powell Joseph E JE 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].
INVESTIGATORS
JOURNAL
VOLUME: 508
ISSUE: 7495
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2014
MONTH: Apr
DAY: 10
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
Cites PLoS Genet. 2013 Feb;9(2):e1003295 23509438
Cites Nature. 2013 Feb 14;494(7436):234-7 23376951
Cites PLoS Genet. 2013 May;9(5):e1003502 23696747
Cites Science. 2013 Jun 21;340(6139):1467-71 23722424
Cites PLoS Genet. 2013;9(3):e1003362 23516379
Cites Nat Genet. 2013 Feb;45(2):124-30 23263488
Cites Bioinformatics. 2000 Jan;16(1):16-23 10812473
Cites Nature. 2003 Mar 20;422(6929):297-302 12646919
Cites Nat Rev Genet. 2004 Aug;5(8):618-25 15266344
Cites EMBO J. 2004 Aug 4;23(15):3103-12 15257297
Cites Nat Genet. 2005 Apr;37(4):413-7 15793588
Cites Nucleic Acids Res. 2005;33(10):3154-64 15933209
Cites Nat Genet. 2006 Apr;38(4):418-20 16532011
Cites Science. 2006 Apr 7;312(5770):111-4 16601193
Cites Bioinformatics. 2007 May 15;23(10):1294-6 17384015
Cites Genome Res. 2007 Jun;17(6):691-707 17567990
Cites PLoS Genet. 2008 May;4(5):e1000062 18451979
Cites PLoS Genet. 2008 Feb;4(2):e1000008 18454194
Cites Annu Rev Genomics Hum Genet. 2008;9:129-42 18505378
Cites Science. 2009 Oct 9;326(5950):289-93 19815776
Cites Am J Hum Genet. 2009 Nov;85(5):750-5 19896111
Cites Science. 2010 Jan 22;327(5964):425-31 20093466
Cites Nat Rev Genet. 2009 Jun;10(6):392-404 19434077
Cites Philos Trans R Soc Lond B Biol Sci. 2010 Apr 27;365(1544):1241-4 20308099
Cites Nature. 2010 Oct 14;467(7317):832-8 20881960
Cites Nat Genet. 2010 Nov;42(11):985-90 20953190
Cites Nat Genet. 2011 Jun;43(6):519-25 21552263
Cites Bioinformatics. 2011 Jun 1;27(11):1462-5 21471009
Cites Bioinformatics. 2011 Aug 1;27(15):2104-11 21653519
Cites Nat Genet. 2011 Aug;43(8):761-7 21743469
Cites PLoS Genet. 2011 Aug;7(8):e1002197 21829388
Cites Am J Hum Genet. 2012 Jan 13;90(1):7-24 22243964
Cites Nat Methods. 2012 May;9(5):473-6 22426492
Cites PLoS One. 2012;7(4):e35430 22563384
Cites Nucleic Acids Res. 2012 Sep;40(16):7690-704 22675074
Cites Nature. 2012 Oct 25;490(7421):535-8 23064225
CommentIn Nature. 2014 Oct 2;514(7520):E5-6 25279929
CommentIn Nature. 2014 Oct 2;514(7520):E3-5 25279928
GRANTS
GRANTID AGENCY COUNTRY
AA014041 NIAAA NIH HHS United States
AA07535 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
DA12854 NIDA NIH HHS United States
GM057091 NIGMS NIH HHS United States
GM099568 NIGMS NIH HHS United States
P01 GM099568 NIGMS NIH HHS United States
R01 GM075091 NIGMS NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Cohort Studies
Epistasis, Genetic genetics
Europe ethnology
Female ethnology
Gene Expression Profiling ethnology
Gene Expression Regulation genetics
Genetic Association Studies genetics
Humans genetics
Linkage Disequilibrium genetics
Male genetics
Pedigree genetics
Polymorphism, Single Nucleotide genetics
Quantitative Trait Loci genetics
Reproducibility of Results genetics
Transcription, Genetic genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
NIHMS554241 NLM
PMC3984375 NLM