journal.pone.0041730.pdf (324.15 kB)
Download file

Hypothesis-Based Analysis of Gene-Gene Interactions and Risk of Myocardial Infarction

Download (324.15 kB)
journal contribution
posted on 24.10.2012, 08:57 by G. Lucas, C. Lluís-Ganella, I. Subirana, M. D. Musameh, J. R. Gonzalez, C. P. Nelson, M. Sentí, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, S. M. Schwartz, D. Siscovick, C. J. O'Donnell, O. Melander, V. Salomaa, S. Purcell, D. Altshuler, N. J. Samani, S. Kathiresan, R. Elosua
The 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).

History

Citation

PLOS ONE, 2012, 7 (8), p. e41730

Version

VoR (Version of Record)

Published in

PLOS ONE

Publisher

Public Library of Science

eissn

1932-6203

Copyright date

2012

Available date

24/10/2012

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041730

Language

eng

Usage metrics

Categories

Keywords

Exports