Variance-component-based meta-analysis of gene–environment interactions for rare variants

Complex diseases are often caused by interplay between genetic and environmental factors. Existing gene–environment interaction (G × E) tests for rare variants largely focus on detecting gene-based G × E effects in a single study; thus, their statistical power is limited by the sample size of the study. Meta-analysis methods that synthesize summary statistics of G × E effects from multiple studies for rare variants are still limited. Based on variance component models, we propose four meta-analysis methods of testing G × E effects for rare variants: HOM-INT-FIX, HET-INT-FIX, HOM-INT-RAN, and HET-INT-RAN. Our methods consider homogeneous or heterogeneous G × E effects across studies and treat the main genetic effect as either fixed or random. Through simulations, we show that the empirical distributions of the four meta-statistics under the null hypothesis align with their expected theoretical distributions. When the interaction effect is homogeneous across studies, HOM-INT-FIX and HOM-INT-RAN have as much statistical power as a pooled analysis conducted on a single interaction test with individual-level data from all studies. When the interaction effect is heterogeneous across studies, HET-INT-FIX and HET-INT-RAN provide higher power than pooled analysis. Our methods are further validated via testing 12 candidate gene–age interactions in blood pressure traits using whole-exome sequencing data from UK Biobank.