Genetics may explain why women have more chronic pain than men

April 8, 2021

Chronic pain is costing the U.S. billions. (AP Photo/Chris Post)

Researchers completing a large-scale genetic study of chronic pain in the U.K. have found differences between men and women that may help explain why the latter experience more chronic pain.

The study, published April 8 in PLOS Genetics, identified more than 30 genetic variations associated with chronic pain in men and women, but only a single gene associated with chronic pain in both, suggesting that chronic pain may have a wholly different genetic basis between the two sexes.

"Chronic pain is roughly twice as prevalent in women compared to men," said first author Keira Johnston, a PhD student studying health and well-being at the University of Glasgow. "Differences are also seen between men and women in terms of response to treatments for pain, whether that be pharmacological or nonpharmacological interventions, and in types of coping mechanisms used when pain is chronic."

In medicine, chronic pain generally refers to persistent pain that lasts more than three months and may occur in association with a previous injury or on its own. It is well understood that chronic pain is more prevalent in women. However, women are frequently assumed to be exaggerating pain, which has impacted their treatment.

"In treating acute pain, I've read accounts of prescriptions tending to be sedatives rather than analgesics when the prescribing clinician is treating a woman, even in post-surgical scenarios," Johnston said, "and of women losing ovaries due to cysts or torsion being repeatedly missed by doctors, despite women relaying that they are in excruciating pain."

A better understanding of the sex-based mechanisms involved in chronic pain could help shake the stigma surrounding chronic pain in women and contribute to better care for patients. Genetics play an important but not fully understood role in these mechanisms.

"Chronic pain is an example of what's known as a complex genetic trait," Johnston said. "This means that it's only partly genetic, and the genetic effect comes from the combination of tiny effects from many thousands of DNA sequence variants."

To study these variants, the researchers conducted a genome-wide association study using data from UK Biobank, an existing biomedical database of over a half-million people. They studied men and women separately, looking for variations in genes and gene activity that were associated with chronic pain in each of these cohorts.

And while they found some similarities, they also found critical differences.

"We found that there were some differences at the genetic, tissue expression and genetic correlation level, between male- and female-stratified chronic pain," Johnston said. "Although the results showed that, overall, the genetic contribution to chronic pain in males and females is largely overlapping, we did find a few genes that were significantly differentially associated with female versus male chronic pain."

In women, 31 genes were associated with chronic pain, while 37 were linked to chronic pain in men. Only one gene was associated with chronic pain in both sexes. The researchers also found that in either sex, these genes were most active in the dorsal root ganglion, a cluster of nerves in the spinal cord that transmit pain signals to the brain. The dorsal root ganglion has emerged in recent years as a potential target for chronic pain treatment.

The findings suggest that while the overall effect of chronic pain genes between men and women is similar, the means by which genes contribute to this effect are different. This provides a point of future study for the sex-based differences in chronic pain.

The findings also support the increasingly accepted hypothesis that a large proportion of chronic pain is generated closer to the brain, in the central nervous system, not from sensory neurons at the site of the pain.

"Another surprising aspect was that there is little genetic evidence for a large sensory nerve component in chronic pain mechanisms — central mechanisms appear to be most important," Johnston said.

The team is next interested in looking for similar differences in data from other countries, as well as examining how variations in the sex chromosomes may be associated with chronic pain. Future studies drawing these associations will also need to consider the complexities of sex and gender itself.

"I think it's important to note that neither sex nor gender are binary, and the relationship between the two is also complex," Johnston said. "We have only been able to study sex/gender differences in a binary way, because that's the data available to us."

But for now, these findings add to a growing body of knowledge on sex and chronic pain.

"Our findings contribute to the knowledge of genetics underlying chronic pain overall and suggest loci of interest and potential future drug targets," Johnston said. "I think our sex-stratified findings require further study but highlight the importance of exploring sex differences in complex traits."

The study, "Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank," published April 8 in PLOS Genetics, was authored by Keira J. A. Johnston, Joey Ward, Rona J. Strawbridge, Daniel J. Smith, Barbara I. Nicholl and Mark E. S. Bailey, University of Glasgow; Pradipta R. Ray and Theodore J. Price, University of Texas at Dallas; Mark J. Adams and Andrew M. McIntosh, University of Edinburgh; and Blair H. Smith, University of Dundee.

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