Suicide risk genes impact evolutionarily conserved survival strategies

Genome-wide association studies (GWAS) and candidate gene analyses have identified possible suicide risk genes that are highly conserved during evolution and enriched in genes essential for life. However, functional roles for these risk genes have not been confirmed and pathways from risk variant to relevant phenotype to suicidality-related behavior remain unknown, highlighting critical gaps in our knowledge. Here, we report findings from the largest behavioral and mechanistic study of suicide risk genes to date. In Caenorhabditis elegans, mutations in risk gene counterparts caused exaggerated threat evaluation (social feeding) and diminished motivation to seek food, which represent ancient strategies for avoiding harm and ensuring survival (foraging). Genetic variation affected neuropeptide (NPY and TGF-β) function and kinase signaling. Remarkably, the altered behaviors were corrected with drugs that reduce suicidal behavior including antidepressants and clozapine. Taken together, these findings reveal that risk genes predisposing a person to take their life normally promote strategies to survive.