Untangling the genetics of fibromyalgia sheds new light on its causes

We are beginning to unravel the genetics of fibromyalgia, a poorly understood condition that causes chronic pain throughout the body. The results of two studies — with millions of participants between them — support the idea that central nervous system dysfunction is a major factor in fibromyalgia. However, previous research suggests that alternative mechanisms, such as autoimmunity, are involved, suggesting the multi-causal complexity of the condition.

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

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

The first study – led by Michael Wainberg at Mount Sinai Hospital in Toronto, Canada – brought together cohorts from several countries, including the US, UK and Finland. The team totaled 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 variants in the genome associated with a higher fibromyalgia risk.

Joel Gelernter of the Yale School of Medicine led the second study, which used datasets from the US and UK. In total, Gelernter and his colleagues looked at 85,139 people with fibromyalgia and 1,642,433 people without, who had a mix of European, Latin American and African ancestry. They found 10 variants associated with fibromyalgia in the European ancestry group, one in the African ancestry group and 12 that were cross ancestry.

Wainberg and Gelernter declined to be interviewed because their studies have not yet been peer-reviewed.

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

In Wainberg and his team’s study, the strongest association was with a variant in a gene called huntingtinwhich can cause the neurodegenerative condition Huntington’s disease. However, this condition is caused by a repeated genetic sequence within huntingtinleading to the production of a defective protein. In contrast, the variant associated with fibromyalgia is a single-letter change in another part of the gene.

But that doesn’t mean that this mutation alone causes fibromyalgia, says Boer. “It has to be combined with other risk factors or other genetics.” There are probably thousands of variants at work, plus external influences, such as exposure to air pollution, she says. Identifying all these variants would require even larger studies.

Despite these shortcomings, the variants involved in Wainberg and his team’s study were all in genes that have roles in neurons, suggesting that many of the key mechanisms of fibromyalgia occur in the brain. Likewise, Gelernter and his team’s study identified variants that have previously been associated with pain and brain-related problems, such as post-traumatic stress disorder and depression.

These findings support an existing hypothesis about fibromyalgia: “something is happening in brain tissue,” says Boer. Follow-up work on the implicated variants could identify key cell types, brain regions and biochemical pathways that can ultimately be targeted for treatments. These are likely years away, warns Boer – unless a known mechanism, targeted by an existing drug, turns out to be involved. Existing interventions focus on exercise, talk therapy, and antidepressants with mixed success.

But mechanisms outside of genetics may also be at work. David Andersson at King’s College London and his team have previously found evidence that fibromyalgia is an autoimmune condition. In 2021, they showed that when antibodies from people with fibromyalgia were injected into mice, they developed painful hypersensitivity and muscle weakness. In September this year, the researchers showed that such mice had abnormal responses to sensations, where nerves that normally respond to light touch also began to respond to cold. This reflects how people with fibromyalgia often feel pain in response to stimuli that other people do not find painful, such as slightly cold temperatures.

“I am very confident in the conclusions from our own work in fibromyalgia, and confident that our published work will be the turning point that marks when the field changed its focus from the central nervous system to autoantibodies [that target the body’s own tissues] and peripheral neuronal [neurons that lie outside of the brain and spinal cord] mechanisms,” says Andersson.

But Boer emphasizes that the latest studies do not disprove it. The researchers set a high bar for statistical significance, so even if we can be sure of the variants they have identified and the bodily mechanisms they implicate, they will have missed many more, she says. Gelernter and his team’s study also identified some variants that have been associated with autoimmune reactions.

Studies like these are “first steps,” says Boer, but they open the door to understanding the roots of fibromyalgia. “What are the paths?” she asks. “And is there anything in there that we can target?”