Gene discovery and pleiotropic architecture of chronic pain in a genome-wide association study of >1.2 million individuals.

Chronic pain is highly prevalent worldwide, and genome-wide association studies (GWAS) have identified a growing number of chronic pain loci. To further elucidate its genetic architecture, we leveraged data from 1,235,695 European ancestry individuals across three biobanks. In a meta-analytic GWAS, we identified 343 independent loci for chronic pain, 92 of which were new. Sex-specific meta-analyses revealed 115 independent loci (12 of which were new) for males (N = 583,066) and 12 loci (two of which were new) for females (N = 241,266). Multi-omics gene prioritization analyses highlighted 490 genes associated with chronic pain through their effects on brain- and blood-specific regulation. Loci associated with increased risk for chronic pain were also associated with increased risk for multiple other traits, with Mendelian randomization analyses showing that chronic pain was causally associated with psychiatric disorders, substance use disorders, and C-reactive protein levels. Chronic pain variants also exhibited pleiotropic associations with cortical area brain structures. This study expands our knowledge of the genetics of chronic pain and its pathogenesis, highlighting the importance of its pleiotropy with multiple disorders and elucidating its multi-omic pathophysiology.