Unraveling 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 instability in the central nervous system is a key factor in fibromyalgia. However, previous research suggests alternative mechanisms, such as autoimmunity, are involved, and indicate the multifaceted complexity of the condition.

Fibromyalgia is thought to affect 2 to 3 percent of people. The reasons for this are unclear, which makes it difficult to treat, but a leading idea is that people with fibromyalgia develop changes in the way their central nervous system processes pain messages, possibly due to 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 on single-lineage variations in the genome, rather than large-scale deletions, which can have a more dramatic effect.

In the first study, led by Michael Weinberg at Mount Sinai Hospital in Toronto, Canada, several countries, including the United States, the United Kingdom, and Finland, came together. The team collected a total of 54,629 people with fibromyalgia, most of whom were of European ancestry, and 2,509,126 people without the condition. From this, the researchers identified 26 variants in the genome associated with increased risk of fibromyalgia.

A second study was led by Joel Gelernter at the Yale School of Medicine, which used datasets from the US and UK. In total, Gelrenter 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 origins. They found 10 variants associated with fibromyalgia in the European ancestry group, one in the African ancestry group and 12 that were cross-ancestry.

Weinberg and Gelrunter declined to be interviewed because their studies have not yet been peer-reviewed.

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

In the study by Weinberg and his team, the strongest association was with a variant in a gene called Huntingtonwhich can cause the neurodegenerative condition Huntington’s disease. However, this condition is caused by frequent genetic mutations within it Huntingtonleading to the production of a 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 alone causes fibromyalgia, Boyer says. “It needs to be linked to other risk factors or other genetics.” She says there are probably thousands of species at work, as well as external influences, such as exposure to air pollution. Larger studies would be needed to identify all these variations.

Despite these shortcomings, the variants in Weinberg and his team’s study were in genes that have roles in neurons, suggesting that many of the key mechanisms of fibromyalgia are found in the brain. Similarly, the study by Gelrunter and his team identified variants that have previously been linked to pain and brain-related issues, such as post-traumatic stress disorder and depression.

The findings reinforce a current hypothesis about fibromyalgia: “something is going on in the brain tissue,” says Boyer. Follow-up work on the underlying variants may identify key cell types, brain regions and biochemical pathways, which may ultimately be targeted for treatment. That’s probably years away, Boyer cautioned—unless it’s known that a known mechanism, targeted by existing drugs, is involved. Current interventions focus on exercise, talk therapy, and antidepressants with mixed success.

However, mechanisms outside of genetics may also be at work. David Anderson and his team at King’s College London 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 produced painful hypersensitivity and muscle weakness. In September of this year, researchers showed that such mice have abnormal responses to sensations, with nerves that normally respond to light touch beginning to respond to cold. This mirrors how people with fibromyalgia often feel pain in response to stimuli that other people don’t find painful, such as slightly cold temperatures.

“I am very confident in the results from my work on fibromyalgia, and believe that our published work will mark the inflection point when the field shifted its focus from the central nervous system to the autonomic bodies. [that target the body’s own tissues] and peripheral neuronal [neurons that lie outside of the brain and spinal cord] mechanism,” says Anderson.

But Boyer stressed that the latest studies don’t invalidate that. The researchers set a high bar for statistical significance, so while we can be confident about the variants they identify, and the physical mechanisms involved, they will miss many more. Also, the study by Jellerinter and his team identified some variants that are associated with autonomic responses.

Studies like these are “first steps,” Boyer says, but they open up the possibility of understanding the roots of fibromyalgia. “What are the routes?” she asks. “And is there anything we can target?”