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

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.