Summary: New genetic research helps explain why women are more likely than men to develop chronic pain conditions. The study also reinforces the central nervous system’s key role in chronic pain and highlights the importance of analyzing sexes separately in genetic research.
Source: PLOS
Researchers report that chronic pain appears to have a different genetic architecture in women and men, which may contribute to the higher prevalence of persistent pain among women.
Keira Johnston of the University of Glasgow and colleagues present these findings in a study published April 8 in PLOS Genetics.
Chronic pain is widespread and can be disabling, with clear differences in how frequently it affects women compared with men. To probe biological explanations for this disparity, the research team conducted the largest sex-stratified genetic study of chronic pain to date, analyzing data separately for women and men.
Using data from the UK Biobank, the investigators examined genetic variants associated with a multisite chronic pain phenotype in 209,093 women and 178,556 men. Their analysis identified 31 genes associated with chronic pain in women and 37 genes associated with chronic pain in men. Only one gene, DCC, showed a significant association in both sexes.
Beyond listing associated genes, the team examined tissue-specific gene activity to understand where these genes are active in the body. Nearly all the genes identified in both sexes were expressed in the dorsal root ganglion (DRG): all 37 male-associated genes and all but one female-associated gene showed activity there. The DRG is a cluster of nerve cell bodies near the spinal cord that relay sensory signals, including pain, from the body to the central nervous system.
These results reinforce earlier evidence from the same research group that chronic pain has a strong central nervous system component—meaning that processes in the brain and spinal cord play a major role in how chronic pain develops and persists. The detection of DRG expression also points to nociceptive mechanisms at the level of peripheral sensory neurons as contributing factors.
Importantly, the study suggests that sex differences in chronic pain are not only clinical but also genetic. The investigators found sex-specific patterns of genetic association and pleiotropy—where the same genetic variation influences multiple traits—and observed that polygenic risk for multisite chronic pain related differently to chronic widespread pain in men and women.
Johnston commented, “Our study highlights the importance of considering sex as a biological variable and showed subtle but interesting sex differences in the genetics of chronic pain.” The authors argue that future research into chronic pain and other complex conditions can gain precision and relevance by using sex-stratified approaches.
Taken together, these findings deepen our understanding of the biological contributors to chronic pain and may guide the development of more targeted treatments. By revealing sex-specific genetic signals and highlighting tissues involved in pain transmission, the study offers concrete leads for laboratory follow-up and potential therapeutic targeting.
About this genetics and pain research news
Source: PLOS
Contact: Keira Johnston – PLOS
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Original Research: Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank. PLOS Genetics. DOI: 10.1371/journal.pgen.1009428 (open access)
Abstract
Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank
Chronic pain affects a large portion of the global population and carries significant social and economic consequences. Although many factors influence susceptibility and mechanisms underlying chronic pain, sex is a consistent modifier of prevalence and presentation—women generally report chronic pain more often than men. To investigate these sex differences at a genetic level, the authors performed a sex-stratified genome-wide association study (GWAS) on a derived Multisite Chronic Pain (MCP) phenotype within the UK Biobank cohort. The study included 178,556 men and 209,093 women and additionally explored sex-specific genetic correlations with psychiatric, autoimmune, and anthropometric traits, as well as the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain.
In men, the analysis identified 123 single-nucleotide polymorphisms (SNPs) at five independent loci that reached genome-wide significance. In women, 286 genome-wide significant SNPs were found at ten independent loci. Meta-analysis combining sex-stratified outputs revealed an additional 87 independent associated SNPs. Gene-level analyses produced sex-specific associations: 31 genes were significantly associated with MCP in females, 37 genes were associated in males, and the single gene DCC was associated in both sexes. There was evidence of sex-specific pleiotropy, and polygenic risk for MCP showed sex-dependent relationships with chronic widespread pain.
Although male and female MCP were highly genetically correlated (rg ≈ 0.92), this correlation was significantly less than one, indicating notable sex-differentiated genetic architecture. All 37 male-associated MCP genes and all but one of the 31 female-associated genes were expressed in the dorsal root ganglion, with some enrichment for expression in sex-specific tissues. These results demonstrate that sex differences in chronic pain extend across single variants, genes, and transcript abundance, and support a substantial central nervous system contribution to chronic pain in both sexes, with potential roles for peripheral nociceptive structures such as the DRG.