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GWAS Uncovers Sex-Based Differences in Genetic Origins of Chronic Pain

NEW YORK — Sex differences in chronic pain may have a genetic origin, a new genome-wide association study has found. The analysis still found, though, that chronic pain in men and women is genetically correlated.

Chronic pain, defined as pain that persists for more than three months, is more common among women, and previous studies have indicated that chronic pain might in part be heritable.

Following on this, researchers from the University of Glasgow and elsewhere conducted a sex-stratified genome-wide association study of multi-site chronic pain using data from the UK Biobank. As they reported on Thursday in PLOS Genetics, the researchers uncovered 31 genes associated with chronic pain among women and 37 among men, with only one gene associated with chronic pain in both men and women. At the same time, though, they found multi-site chronic pain between men and women was highly genetically correlated.

"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," first author Keira Johnston, a PhD student at Glasgow and the University of Edinburgh, said in a statement.

She and her colleagues conducted two GWAS of multisite chronic pain, one of 178,566 men and one of 209,093 women from the UK Biobank. Among men, they identified 123 SNPs at five loci associated with multisite pain, while among women, they uncovered 286 SNPs at 10 loci. A further 257 SNPs had some suggestive association with multisite pain in men or women.

In a meta-analysis, they further found 49 lead SNPs across 46 genomic loci to be linked to multisite chronic pain.

Through a gene-level association analysis, the researchers searched for genes enriched for variants linked to multi-site chronic pain. Among women, they uncovered 37 genes significantly enriched for such variants and, among men, 31 genes. Only one gene — DCC — was significantly associated with multisite chronic pain in both men and women, underscoring the potential genetic basis of sex differences in chronic pain.

At the transcriptome level, using GTEx datasets and other gene expression datasets, the researchers found that most of the genes associated with multisite chronic pain in either men or women are active in the brain and the dorsal root ganglion, a cluster of nerves in the spinal cord that transmits pain signals. This, they added, suggests that multi-site chronic pain originates from the brain or central nervous system, rather than other organ systems.

Additionally, some genes were involved in immune function and others had increased expression in sex-specific tissues like the testis and ovary, suggesting they could be influenced by the presence of androgen or estrogen.

Despite these differences, multi-site chronic pain among men and women was highly genetically correlated. In an email, Johnston estimated that genetic overlap between the two was about 98 percent. In addition, multi-site chronic pain among men and women had similar genetic correlations with other conditions, especially psychiatric conditions like major depression, anxiety, neuroticism, and suicidality.

"I think one thing that was quite surprising was actually the similarities between male and female-stratified chronic pain, at the genetic variation level, despite the subtle differences we saw," Johnston said.

She added she and her colleagues hope to replicate their findings using other large cohorts. Further, as their analysis focused on autosomal variation, they also would like to examine X chromosome-linked genetic variation that may influence chronic pain in men and women.

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