Differentiating genetic and gene-environment interaction profiles of physical and mental health disorders

Predisposition to adult chronic physical and mental health disorders is shaped by genetics, environmental exposures, and their interactions. However, it remains unclear whether the same genetic variants associated with disease risk also influence how individuals respond to environmental exposures, such as early life adversity. This study examined whether genetic variants associated with disease risk overlap with those that modulate the effects of early life adversity. Methods: Analyses were conducted in the UK Biobank, a population-based cohort of adults aged 37-73 years at recruitment. A total of 180,129 participants were included, comprising 22,372 individuals reporting early adversity and 157,757 who did not. Genome-wide association studies (GWAS) and genome-wide environment interaction studies (GWEIS) were performed for four health outcomes based on hospital diagnoses: cardiovascular disorders, type 2 diabetes, mood disorders, and neurotic disorders. Early life adversity was assessed using a validated questionnaire item capturing feelings of being hated or unloved during childhood. Results: We demonstrate that genetic variants identified in GWAS do not overlap with those detected in GWEIS, even at a nominal significance level (p < 5×10⁻⁵). SNP-based heritability was detectable for the main effect analyses but not for the interaction analyses, being greater for physical diseases than for mental health conditions. Conclusions: Genetic variants associated with disease risk do not capture context-dependent genetic effects. This has important implications for approaches relying on GWAS-derived signals, including risk prediction and biological interpretation. Integrating environmental context into genetic analyses is critical for understanding chronic disease etiology and identifying context-specific genetic risk factors. Many common adult diseases, such as heart disease, diabetes, and mental health disorders, are influenced by both genetics and early life experiences. However, it is not clear whether the same genetic factors that increase disease risk also affect how people respond to early life adversity. In this study, we analyzed genetic data from more than 180,000 participants in the UK Biobank. We compared genetic factors linked to disease risk with those involved in how early adversity influences disease development. We found that these two sets of genetic factors are largely different for both physical and mental health conditions. These findings suggest that different biological mechanisms may underlie disease risk and responses to early adversity, which may help guide future research and prevention. Barth, Miguel et al. analyze genetic data from over 180,000 UK Biobank participants to compare variants associated with disease risk (GWAS) with those modifying the effects of early life adversity (GWEIS). Across both physical and mental disorders, the two sets of variants are largely distinct.