Evaluating the heterogeneous treatment effects of major depression polygenic risk scores on self-harm using causal forest

Self-harm, defined as non-fatal self-inflicted harm regardless of suicidal intent, is a critical global health issue influenced by the interaction between genetic and environmental factors.
This study investigates the causal effect of major depression polygenic risk scores (MD PRS) on self-harm in individuals of European ancestry and explores how environmental and personal factors moderate this effect.
Using data from 91,778 UK Biobank participants, we compared the top 10% with the highest MD PRS (the genetically vulnerable group) against the remainder. The causal relationship was examined using a causal forest approach to estimate average and heterogeneous treatment effects across non-genetic contributors.
Higher MD PRS was associated with an increased risk of self-harm. Significant heterogeneity was observed: the association was stronger among individuals exposed to physical violence or partner belittlement, but weaker among older adults and those with higher income.
These findings highlight the importance of personalized prevention. Genetic vulnerability to depression reflects a heightened sensitivity to adverse environments, suggesting that genetic risk should be considered alongside trauma and socioeconomic contexts.