Robust Interaction Testing using Sample Splitting (RITSS) identifies widespread gene-by-sex interactions in lung function

The identification and understanding of gene-environment interactions can provide insights into the causal pathways and mechanisms underlying complex diseases. However, testing for gene-environment interaction remains challenging since statistical power is limited and gene-environment correlations can introduce false positive interaction findings.
We recently proposed RITSS (Robust Interaction Testing using Sample Splitting), a gene-environment interaction testing methodology for quantitative traits that tackles these challenges by jointly analyzing sets of genetic variants using sample splitting combined with screening approaches and robust test statistics.
We applied RITSS to lung function data (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC) in the UK Biobank. RITSS identified highly significant interactions between previously reported genetic variants for lung function and sex. These interactions are characterized by small effects on the single variant level but follow a systematic structure that results in an aggregated joint effect. Specifically, we observed shared genetic factors between males and females with an identical effect direction but a larger magnitude in males. This phenomenon was recently introduced in the literature as amplification.
While recent biobank analyses were largely unsuccessful in identifying sex-specific genetic variants on the single variant level, the systematic structure of amplification identified by our RITSS approach could potentially point toward the underlying mechanisms of sex-differential effects.
Further, this new gene-environment interaction research direction of amplification opens the path to a variety of promising follow-up analyses to investigate the related genes, pathways, and consistency of sex-specific genetic architecture across different lung function traits.