A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects
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 detec...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-07-01
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| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00225/full |
| _version_ | 1811233140010647552 |
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| author | Urko M Marigorta Greg eGibson |
| author_facet | Urko M Marigorta Greg eGibson |
| author_sort | Urko M Marigorta |
| collection | DOAJ |
| description | 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 2,500 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 to 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. |
| first_indexed | 2024-04-12T11:16:29Z |
| format | Article |
| id | doaj.art-2a68537323a04a4298ced7b32d4b5916 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-12T11:16:29Z |
| publishDate | 2014-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-2a68537323a04a4298ced7b32d4b59162022-12-22T03:35:29ZengFrontiers Media S.A.Frontiers in Genetics1664-80212014-07-01510.3389/fgene.2014.0022597648A simulation study of gene-by-environment interactions in GWAS implies ample hidden effectsUrko M Marigorta0Greg eGibson1Georgia Institute of TechnologyGeorgia Institute of TechnologyThe 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 2,500 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 to 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.http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00225/fullObesityGWASBMIcomplex disease geneticsdecanalizationGene-by-environment |
| spellingShingle | Urko M Marigorta Greg eGibson A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects Frontiers in Genetics Obesity GWAS BMI complex disease genetics decanalization Gene-by-environment |
| title | A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects |
| title_full | A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects |
| title_fullStr | A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects |
| title_full_unstemmed | A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects |
| title_short | A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects |
| title_sort | simulation study of gene by environment interactions in gwas implies ample hidden effects |
| topic | Obesity GWAS BMI complex disease genetics decanalization Gene-by-environment |
| url | http://journal.frontiersin.org/Journal/10.3389/fgene.2014.00225/full |
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