Sex-Stratified Genome-Wide Association Study of Multisite Chronic Pain in UK Biobank

Abstract

Chronic pain is highly prevalent worldwide and imparts significant socioeconomic and public health burden and is more prevalent in women than in men. Factors that influence susceptibility and mechanisms of chronic pain development, are not fully understood. 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. Genetic correlations between MCP in each sex and a range of psychiatric, autoimmune, and anthropometric phenotypes were examined. The relationship between female and male MCP, and chronic widespread pain was investigated using polygenic risk scoring. Expression of sex-specific MCP-associated loci in a range of tissues was examined using GTEx, and separately in neural and non-neural human tissues with assessment for dorsal-root ganglion (DRG) enrichment. For genes enriched for neural-tissue expression the full GTEx database was queried for sex-differential gene expression in CNS regions, and for high expression in sex-specific tissues. Expression in neural mouse tissue was also examined for orthologs of these genes. 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 output found 87 independent SNPs to be significantly associated with MCP. We found sex-specific MCP-associated genes, with 31 genes and 37 genes associated with female and male MCP respectively and one gene associated with MCP in both sexes (DCC). 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 rg significantly less than 1. All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the DRG, and many showed elevated expression in sex-specific tissues. Overall, findings indicate sex differences in chronic pain at the SNP, gene and transcriptomic level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong nervous-system component to chronic pain in both sexes, emphasise the importance of the DRG, and indicate specific loci which may play a specialised role in nociception.