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Chronic Pain Could Have a Unique Genetic Basis in Women

9 APRIL 2021

A sweeping meta-analysis of data from the United Kingdom Biobank has found a different genetic basis for chronic pain in women compared to men.

The results are still preliminary, but to date, this is one of the largest genetic studies on chronic pain to analyze the female and male sex separately.

 

"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," says population geneticist Keira Johnston from the University of Glasgow in Scotland.

Chronic pain conditions are among the most prevalent, disabling, and expensive conditions in public health. In the United States, chronic pain affects more people than heart disease, diabetes, and cancer combined, and yet it receives a fraction of the overall funding

Even when studies are done, they often overlook underlying sex differences, and that's a huge and detrimental oversight. Compared to men, women are far more likely to develop multiple chronic pain disorders, and yet historically, 80 percent of all pain studies have been conducted on male mice or male humans. This means we know very little about how and why females are suffering more and what treatments can help them best.

While there are probably multiple biological and psychosocial processes in this sex discrepancy, the current genome-wide study suggests there's a genetic factor in the mix, too.

Comparing gene variants associated with chronic pain in 209,093 women and 178,556 men from the UK Biobank, researchers have attempted to find at least part of the answer in our biology.

 

In the end, researchers found 31 genes associated with chronic pain in women and 37 genes associated with chronic pain in men with barely any overlap. The authors admit some of the differences here might stem from their lower male sample size, but the results are nonetheless intriguing. 

When researchers tested the expression of all these genetic variants across various tissues from mice and humans, they noticed the vast majority were active in a cluster of nerves within the spinal cord, known as the dorsal root ganglion, which transmits messages from the body to the brain.

Several genes in the male-only or female-only list were associated with psychiatric issues or immune function, but only one gene, known as DCC, was in both lists.

DCC encodes for a receptor that binds with a protein crucial for the development of the nervous system, especially the dopaminergic system; as well as being a reward center, the latter has recently been connected to pain modulation in the body.

DCC is also thought to be a risk gene for the pathology of depression, and DCC mutations appear in those with congenital mirror movement disorder, which results in movements on one side of the body being replicated on the other side. 

 

How exactly DCC is connected to chronic pain remains unclear, but the authors say their results support several theories "of strong nervous system and immune involvement in chronic pain in both sexes", which they hope will be used to develop better treatments in the future.

If chronic pain is more strongly associated with immune function in women, for instance, the side-effects of immune-targeting drugs may be very different to men. On the other hand, treatments such as chronic opioid use might also have different outcomes. Opioids are known to adversely affect immune function, which suggests they could make things worse and not better for women in chronic pain.

For right now at least, these are just ideas. Way more pain research needs to be done and far more of it needs to be conducted among women before we can really begin to understand the real sex discrepancies at play and what we can do about it.

"All of these lines of evidence, together, suggest putative central and peripheral neuronal roles for some of these genes, many of which have not been historically well studied in the field of chronic pain," the authors conclude.

The study was published in PLOS Genetics.