Abstract
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 rg 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.
Highlights
Chronic pain is widely defined as pain persisting beyond 3 months [1,2], and can be a primary disorder [3] or secondarily associated with injury, surgery or a range of medical conditions
All 15 of these loci were differentially associated with sex —none of the genome-wide significant single nucleotide polymorphism (SNP) at these loci had p < 5 x 10−8 in the genome-wide association studies (GWAS) conducted in the opposite sex
We examined transcriptome abundance of key sex-differential MCPassociated genes in a range of neural and non-neural tissues, including dorsal root ganglion (DRG), an important nervous system component in chronic pain which is not part of the GTEx resource and so may be understudied in GWASs with follow-up conducted solely using FUMA
Summary
Chronic pain is widely defined as pain persisting beyond 3 months [1,2], and can be a primary disorder [3] or secondarily associated with injury, surgery or a range of medical conditions. Factors influencing susceptibility to chronic pain, and the mechanisms underlying its development and maintenance, are not fully understood. Sex as a biological variable has wide-ranging effects on the functioning of the genome and on resultant phenotypes. These effects can be mediated via sex-differential gene expression [20,21], sex differences in methylation [22,23,24,25,26] and expression quantitative trait locus (eQTL) effects [27,28], or differing levels and actions of hormones [29,30]. Chronic pain exhibits sex-related prevalence differences, and is more common in women than in men [32,33,34]. In addition to differences in prevalence between the sexes, sex differences in underlying pain mechanisms and their modulation by immune cells have been recently reported [36,37,38], and immune responses in general can differ by sex [39]
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