Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an r(g) of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception. Author summary Chronic pain is a highly prevalent and debilitating condition, which is more common in women than in men. Sex differences in this condition may be a result of several factors, including differences between the sexes in genetic variation related to chronic pain and gene expression differences related to sex. To explore sex differences in chronic pain from a genetic perspective, we looked for genetic variants associated with chronic pain in men and women separately in a large general-population cohort, and compared the variants we identified between the sexes. We assessed the degree of overlap between genetic variants associated with chronic pain in each sex and those associated with a wide range of other traits, including major depression, body-mass index and suicidality. We also investigated gene expression patterns across a range of tissues for genes associated with chronic pain in each sex, in particular examining expression in neural and non-neural human and mouse tissues and assessing the degree of Dorsal Root Ganglion (DRG) enrichment, an important peripheral nervous system component involved in chronic pain. This work contributes to understanding of chronic pain as a trait and of sex differences in chronic pain at the levels of genetics and gene expression.

Automated summary

This study found significant differences in chronic pain between males and females, with gender-specific genes and SNPs closely associated with chronic pain. While male and female chronic pain were highly genetically correlated, there were differences between the sexes.