Integrative Mendelian randomization for detecting exposure-by-group interactions using group-specific and combined summary statistics.

Interactions between risk factors and covariate-defined groups are commonly observed in complex diseases. Existing methods for detecting interactions typically require individual-level data. The data availability and the measurements of risk exposures and covariates often limit the power and applicability in assessing interactions. To address these limitations, we propose int2MR, an integrative Mendelian randomization (MR) method that leverages GWAS summary statistics on exposure traits and group-separated and/or combined GWAS statistics on outcome traits. The int2MR can assess a broad range of risk exposure effects on diseases and traits, revealing interactions unattainable with incomplete or limited individual-level data. Simulation studies demonstrate that int2MR effectively controls type I error rates under various settings while achieving considerable power gains with the integration of additional group-combined GWAS data. We applied int2MR to two data analyses. First, we identified risk exposures with sex-interaction effects on ADHD, and our results suggested potentially elevated inflammation in males. Second, we detected age-group-specific risk factors for Alzheimer's disease pathologies in the oldest-old (age 95+); many of these factors were related to immune and inflammatory processes. Our findings suggest that reduced chronic inflammation may underlie the distinct pathological mechanisms observed in this age group. The int2MR is a robust and flexible tool for assessing group-specific or interaction effects, providing insights into disease mechanisms.