Leveraging phenotypic variability to identify genetic interactions in human phenotypes.

TitleLeveraging phenotypic variability to identify genetic interactions in human phenotypes.
Publication TypeJournal Article
Year of Publication2021
AuthorsMarderstein AR, Davenport ER, Kulm S, Van Hout CV, Elemento O, Clark AG
JournalAm J Hum Genet
Date Published2021 01 07
KeywordsBiological Variation, Population, Gene-Environment Interaction, Genome-Wide Association Study, Genotype, Humans, Phenotype, Quantitative Trait Loci, Quantitative Trait, Heritable

Although thousands of loci have been associated with human phenotypes, the role of gene-environment (GxE) interactions in determining individual risk of human diseases remains unclear. This is partly because of the severe erosion of statistical power resulting from the massive number of statistical tests required to detect such interactions. Here, we focus on improving the power of GxE tests by developing a statistical framework for assessing quantitative trait loci (QTLs) associated with the trait means and/or trait variances. When applying this framework to body mass index (BMI), we find that GxE discovery and replication rates are significantly higher when prioritizing genetic variants associated with the variance of the phenotype (vQTLs) compared to when assessing all genetic variants. Moreover, we find that vQTLs are enriched for associations with other non-BMI phenotypes having strong environmental influences, such as diabetes or ulcerative colitis. We show that GxE effects first identified in quantitative traits such as BMI can be used for GxE discovery in disease phenotypes such as diabetes. A clear conclusion is that strong GxE interactions mediate the genetic contribution to body weight and diabetes risk.

Alternate JournalAm J Hum Genet
PubMed ID33326753
PubMed Central IDPMC7820920