Unraveling the Genetic Basis of Self-Harm Phenotypes: New Perspectives on Its Links to Depression and Chronic Pain.

Background: Self-harm is a complex behavior with substantial mental health implications across the lifespan, including among middle-aged and older adults, an often underrecognized population in suicide prevention efforts. While chronic pain and depression are known correlates of self-harm, the underlying genetic and mechanistic relationships among these conditions remain poorly understood. Methods: In this study, we focused on self-harm as the primary outcome and investigated whether depression genetically mediates the link between chronic pain and self-harm risk. Using a large-scale dataset from the UK Biobank (>500,000 individuals), we applied an integrative analytic framework combining polygenic risk scoring, genetic correlation, causal inference, and genomic structural equation modeling (SEM). Results: Both depression and chronic pain were significantly associated with self-harm phenotypes in epidemiological analyses, and these associations remained robust after accounting for psychiatric comorbidities, including anxiety, as well as analgesic and psychotropic medication use. Genetic analyses further supported depression as a key mediator linking chronic pain to self-harm phenotypes, with evidence from genetic correlation, Mendelian randomization, and genomic SEM analyses. Genomic SEM identified candidate genes and enriched pathways involved in synaptic signaling and neurodevelopment, pointing to a shared biological basis. Conclusions: These findings suggest a new depression-mediated genetic model of self-harm, emphasizing the importance of integrated psychiatric and somatic screening to inform early intervention strategies in aging populations.