Unpicking the genetics of fibromyalgia sheds new light on its causes

We are beginning to uncover the genetics of fibromyalgia, a poorly understood disease that causes chronic pain all over the body. Findings from two studies involving millions of participants support the idea that central nervous system dysfunction is a major factor in fibromyalgia. However, previous studies suggest that alternative mechanisms, such as autoimmunity, are involved, hinting at the multi-causal complexity of this condition.

Fibromyalgia It is thought to affect 2 to 3 percent of people. Its causes are unclear, making treatment difficult, but the leading idea is that people with fibromyalgia have developed changes in the way their central nervous system processes pain messages, perhaps due to infection or changes in the gut microbiome.

To understand the role geneticsTwo groups of researchers conducted genome-wide association studies to identify genetic variants that are more common in people with fibromyalgia. Both studies focused only on single letter variations in the genome, rather than other variants such as large-scale deletions, which can have a more dramatic effect.

First study led Michael Weinberg at Mount Sinai Hospital in Toronto, Canada – recruited cohorts from different countries, including the US, UK and Finland. The team recruited a total of 54,629 people with fibromyalgia, most of whom were of European descent, and 2,509,126 people without the condition. From this, the researchers identified 26 genomic variants associated with a higher risk of fibromyalgia.

Joel Gelernter at Yale School of Medicine led the second study, which used datasets from the US and UK. In total, Gelernter and colleagues studied 85,139 people with fibromyalgia and 1,642,433 people without fibromyalgia who were of mixed European, Hispanic, and African ancestry. They found 10 variants associated with fibromyalgia in the European ancestry group, one in the African ancestry group, and 12 cross-ancestry variants.

Weinberg and Gelernter declined to be interviewed because their research has not yet been peer-reviewed.

“Both studies, in terms of sample size, are really great,” says Cindy Farmer at the Erasmus Medical Center in Rotterdam, the Netherlands.

In Weinberg and his team's study, the strongest link was to a gene variant called Huntingtinwhich can cause the neurodegenerative condition Huntington's disease. However, this condition is caused by a repeating genetic sequence within Huntingtinwhich leads to the production of defective protein. In contrast, the variant associated with fibromyalgia is a single-letter change in a different part of the gene.

But that doesn't mean the mutation itself causes fibromyalgia, Boer says. “It needs to be combined with other risk factors or other genetics.” There are probably thousands of options, plus outside influences such as exposure to air pollutionshe says. Identifying all of these options will require even larger studies.

Despite these shortcomings, all of the variants implicated in Weinberg and his team's study were in genes that play a role in neurons, suggesting that many of the key mechanisms of fibromyalgia occur in brain. Likewise, Gelernter and his team's research identified variants that have previously been linked to pain and brain-related problems such as post-traumatic stress disorder and depression.

These results support the current hypothesis about fibromyalgia: “there's something going on in the brain tissue,” Boer says. Follow-up work on the variants involved could identify key cell types, brain regions and biochemical pathways that could ultimately be targeted for treatment. That will likely be many years away, warns Boyer, unless a known mechanism that is targeted by an existing drug turns out to be involved. Existing interventions focus on exercise, talk therapy and antidepressants with varying success.

However, mechanisms outside of genetics may also be at work. David Andersson from King's College London and his team previously found evidence that fibromyalgia is an autoimmune disease. In 2021, they showed that when mice were injected with antibodies from people with fibromyalgia, they developed painful hypersensitivity and muscle weakness.. This September, researchers showed that these mice exhibit abnormal responses to sensation, with nerves typically responding to light touch. I'm also starting to react to the cold. This reflects how people with fibromyalgia often feel pain in response to stimuli that other people do not consider painful, such as a slight drop in temperature.

“I am very confident in the findings of our own work in fibromyalgia and confident that our published work will mark a watershed moment as the field shifts its focus from the central nervous system to autoantibodies. [that target the body’s own tissues] and peripheral neurons [neurons that lie outside of the brain and spinal cord] mechanisms,” says Andersson.

But Boer emphasizes that the latest research does not refute this claim. The researchers set the bar high for statistical significance, so while we can be confident in the variants they identified and the bodily mechanisms associated with them, they will miss much more, she says. In addition, Gelernter and his team's research identified some variants associated with autoimmune reactions.

Research like this is “first steps,” Boer says, but it opens the door to understanding the roots of fibromyalgia. “Which ways?” she asks. “And is there anything there that we can target?”