Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies

Gene-environment (GxE) interaction is one potential explanation for the missing heritability problem. A popular approach to genome-wide environment interaction studies (GWEIS) is based on regression models involving interactions between genetic variants and environment variables. Unfortunately, GWEIS encounters systematically inflated (or deflated) test statistics more frequently than a marginal association study. The problematic behavior may occur due to poor specification of the null model (i.e. the model without genetic effect) in GWEIS. Improved null model specification may resolve the problem, but the investigation requires many time-consuming analyses of genome-wide scans, e.g. by trying out several transformations of the phenotype. It is therefore helpful if we can predict such problematic behavior beforehand. We present a simple closed-form formula to assess problematic behavior of GWEIS under the null hypothesis of no genetic effects. It requires only phenotype, environment variables, and covariates, enabling quick identification of systematic test statistic inflation or deflation. Applied to real data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), our formula identified problematic studies from among hundreds GWEIS considering each metabolite as the environment variable in GxE interaction. Our formula is useful to quickly identify problematic GWEIS without requiring a genome-wide scan.