Investigating genetic overlap of multidimensional pain and suicidal behaviors in >2 million individuals

Although chronic pain is a major risk factor for suicidal behaviors, the shared genetic underpinnings of these phenotypes are poorly understood. This study leveraged genome-wide association data to examine the shared genetic architecture between multidimensional pain (MP), capturing broad genetic liability to chronic pain ( n  = 1,235,695), and suicidal behaviors, including suicide attempt (SA, n  = 787,974) and suicide death (SD, n  = 18,223). Integrative cross-trait genetic analyses revealed substantial polygenic overlap between MP and both suicidal behaviors, and identified 76 (244 genes) and 10 (27 genes) distinct shared loci for SA and SD, respectively. The genes mapped to the shared SA loci were enriched in neuronal and synaptic pathways, and integration of multi-omics data further prioritized 10 genes, providing convergent molecular context relevant to the neurobiological and behavioral pathways implicated in the association between pain liability and SA. Mendelian randomization analyses supported a potential causal relationship between MP and both suicidal behaviors, with asymmetric bidirectional effects for MP and SA. Mediation analyses further indicated that 14 health-related traits, including psychological and substance-related behaviors, partially mediated the association between MP and SA. Together, these findings reveal shared genetic architecture between MP and suicidal behaviors, with the association partially mediated by convergent neurobiological and potentially modifiable behavioral pathways relevant to prevention and therapeutic efforts.