title: A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects.
abstract: The switch to a modern lifestyle in recent decades has coincided with a rapid increase in prevalence of obesity and other diseases. These shifts in prevalence could be explained by the release of genetic susceptibility for disease in the form of gene-by-environment (GxE) interactions. Yet, the detection of interaction effects requires large sample sizes, little replication has been reported, and a few studies have demonstrated environmental effects only after summing the risk of GWAS alleles into genetic risk scores (GRSxE). We performed extensive simulations of a quantitative trait controlled by 2500 causal variants to inspect the feasibility to detect gene-by-environment interactions in the context of GWAS. The simulated individuals were assigned either to an ancestral or a modern setting that alters the phenotype by increasing the effect size by 1.05-2-fold at a varying fraction of perturbed SNPs (from 1 to 20%). We report two main results. First, for a wide range of realistic scenarios, highly significant GRSxE is detected despite the absence of individual genotype GxE evidence at the contributing loci. Second, an increase in phenotypic variance after environmental perturbation reduces the power to discover susceptibility variants by GWAS in mixed cohorts with individuals from both ancestral and modern environments. We conclude that a pervasive presence of gene-by-environment effects can remain hidden even though it contributes to the genetic architecture of complex traits.
authors.affiliation: Center for Integrative Genomics, School of Biology, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: Urko M
authors.initials: UM
authors.lastname: Marigorta
authors.affiliation: Center for Integrative Genomics, School of Biology, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Gibson
keywords: GWAS; complex disease; decanalization; environmental perturbation; gene-by-environment; genetic risk score; modern lifestyle; obesity
references.citation: Genetics. 2004 Dec;168(4):2271-84
references.pmid: 15611191
references.citation: Gastroenterology. 2007 May;132(6):2087-102
references.pmid: 17498505
references.citation: Nat Genet. 2010 Nov;42(11):937-48
references.pmid: 20935630
references.citation: Nat Genet. 2008 May;40(5):616-22
references.pmid: 18385676
references.citation: BMJ. 2014 Mar 19;348:g1610
references.pmid: 24646652
references.citation: Am J Epidemiol. 2013 Jan 15;177(2):103-15
references.pmid: 23255780
references.citation: PLoS Med. 2011 Nov;8(11):e1001116
references.pmid: 22069379
references.citation: Curr Nutr Rep. 2012 Jun 26;1:184-196
references.pmid: 24392269
references.citation: Nat Genet. 2010 Jul;42(7):570-5
references.pmid: 20562874
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references.pmid: 22243964
references.citation: Diabetes. 2008 Jan;57(1):95-101
references.pmid: 17942823
references.citation: N Engl J Med. 2012 Oct 11;367(15):1387-96
references.pmid: 22998338
references.citation: Transl Psychiatry. 2013 Aug 13;3:e290
references.pmid: 23942621
references.citation: Nat Genet. 2012 Mar 25;44(5):483-9
references.pmid: 22446960
references.citation: JAMA. 2014 Jun 4;311(21):2173-4
references.pmid: 24893084
references.citation: PLoS Med. 2011 Oct;8(10):e1001106
references.pmid: 22022235
references.citation: PLoS One. 2011;6(6):e20816
references.pmid: 21738588
references.citation: Physiol Res. 2011;60(1):175-83
references.pmid: 20945952
references.citation: Int J Epidemiol. 2001 Oct;30(5):1035-40
references.pmid: 11689518
references.citation: Int J Epidemiol. 2003 Feb;32(1):51-7
references.pmid: 12690008
references.citation: PLoS One. 2012;7(7):e40503
references.pmid: 22848382
references.citation: Nat Rev Genet. 2009 Feb;10(2):134-40
references.pmid: 19119265
references.citation: Diabetes Care. 2013 May;36(5):1413-21
references.pmid: 23613601
references.citation: Nature. 2010 Oct 14;467(7317):832-8
references.pmid: 20881960
references.citation: Lancet. 2007 Dec 8;370(9603):1929-38
references.pmid: 18063029
references.citation: Nat Rev Genet. 2004 Sep;5(9):681-90
references.pmid: 15372091
references.citation: Am J Clin Nutr. 2009 May;89(5):1453-8
references.pmid: 19279076
references.citation: PLoS One. 2010 May 20;5(5):e10746
references.pmid: 20505766
references.citation: PLoS One. 2011;6(11):e27135
references.pmid: 22087252
references.citation: Transl Psychiatry. 2011 Jun 28;1:e14
references.pmid: 22832430
references.citation: Mol Neurobiol. 2011 Oct;44(2):160-5
references.pmid: 21499988
references.citation: Hum Genet. 2013 May;132(5):495-508
references.pmid: 23334806
references.citation: Obesity (Silver Spring). 2011 Sep;19(9):1866-72
references.pmid: 21593801