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dc.contributor.authorLucas, G
dc.contributor.authorLluís-Ganella, C
dc.contributor.authorSubirana, I
dc.contributor.authorMusameh, MD
dc.contributor.authorGonzalez, JR
dc.contributor.authorNelson, CP
dc.contributor.authorSentí, M
dc.contributor.authorMyocardial Infarction Genetics Consortium
dc.contributor.authorWellcome Trust Case Control Consortium
dc.contributor.authorSchwartz, SM
dc.contributor.authorSiscovick, D
dc.contributor.authorO'Donnell, CJ
dc.contributor.authorMelander, O
dc.contributor.authorSalomaa, V
dc.contributor.authorPurcell, S
dc.contributor.authorAltshuler, D
dc.contributor.authorSamani, NJ
dc.contributor.authorKathiresan, S
dc.contributor.authorElosua, R
dc.date.accessioned2017-07-24T14:14:53Z
dc.date.issued2012
dc.description.abstractThe genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3-2.0, depending on allele frequency and interaction model).en_GB
dc.description.sponsorshipThe Myocardial Infarction Genetics Consortium (MIGen) was funded by grant R01 HL087676 from the National Institutes of Health, USA. The Wellcome Trust Case-Control Consortium 2 was funded by the Wellcome Trust under award 085475. This work was supported by a grant from ACC1O´ (RD08-1-0024), the European Regional Development Fund (ERDF-FEDER), the Spanish Ministry of Science and Innovation through the Carlos III Health Institute (CIBER Epidemiologı´a y Salud Pu´blica, Red HERACLES RD06/0009, PI061254, PI09/90506 and the GENOMet network, MTM2010-09526-E), the Catalan Research and Technology Innovation Interdepartmental Commission (SGR 1195) and Fundacio´ La Marato´ de TV3 (1081810; 080431). VS was supported by the Academy of Finland (grants # 129494 and 139635). GL was funded by the Juan de la Cierva Program, Ministerio de Educacio´n (JCI-2009-04684).en_GB
dc.identifier.citationVol. 7, e41730en_GB
dc.identifier.doi10.1371/journal.pone.0041730
dc.identifier.otherPONE-D-12-08719
dc.identifier.urihttp://hdl.handle.net/10871/28599
dc.language.isoenen_GB
dc.publisherPublic Library of Scienceen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/22876292en_GB
dc.rightsThis is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.en_GB
dc.subjectEpistasis, Geneticen_GB
dc.subjectGenetic Predisposition to Diseaseen_GB
dc.subjectGenome-Wide Association Studyen_GB
dc.subjectGenotypeen_GB
dc.subjectHumansen_GB
dc.subjectMyocardial Infarctionen_GB
dc.subjectPolymorphism, Single Nucleotideen_GB
dc.subjectReproducibility of Resultsen_GB
dc.subjectRisken_GB
dc.subjectRisk Factorsen_GB
dc.titleHypothesis-based analysis of gene-gene interactions and risk of myocardial infarctionen_GB
dc.typeArticleen_GB
dc.date.available2017-07-24T14:14:53Z
dc.identifier.issn1932-6203
exeter.place-of-publicationUnited Statesen_GB
dc.descriptionThis is the final version of the article. Available from the publisher via the DOI in this record.en_GB
dc.identifier.journalPLoS Oneen_GB
dc.identifier.pmcidPMC3410908
dc.identifier.pmid22876292


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