Recent advances in our understanding of the genetics behind fibromyalgia, a poorly understood disorder characterized by widespread chronic pain, are emerging. Two large-scale studies have reinforced the notion that dysfunctions within the central nervous system significantly contribute to fibromyalgia. Nonetheless, other studies have indicated the involvement of alternative mechanisms such as autoimmunity, highlighting the complex, multi-faceted nature of this ailment.

Fibromyalgia is believed to impact 2-3% of the population. While the exact cause remains a mystery, treatment is challenging. A prevailing hypothesis suggests that individuals with fibromyalgia may experience alterations in how their central nervous system interprets pain signals, potentially triggered by infections or changes in gut microbiota.

To investigate the genetics involved, two research teams undertook genome-wide association studies (GWAS) to pinpoint genetic variations prevalent in fibromyalgia patients. Their focus rested primarily on single-letter mutations rather than more extensive genomic alterations which might have more pronounced effects.

The first study, led by Michael Weinberg at Mount Sinai Hospital in Toronto, Canada, encompassed participants from various countries, including the United States, the United Kingdom, and Finland. This team gathered data from 54,629 individuals with fibromyalgia, primarily of European descent, and compared it to 2,509,126 individuals without the condition. Their findings revealed 26 genetic mutations linked to a higher risk of fibromyalgia.

Meanwhile, Joel Gelernter from Yale School of Medicine directed a second study utilizing datasets from the U.S. and the U.K. Their research involved 85,139 patients with fibromyalgia and 1,642,433 controls of mixed European, Latin American, and African ancestries. They identified 10 mutations associated with fibromyalgia among the European group, one in the African group, and 12 across diverse ancestries.

Both Weinberg and Gelernter opted not to give interviews as their studies await peer review.

“Both studies are truly commendable in terms of their participant numbers,” remarked Cindy Bohr from Erasmus Medical Center in Rotterdam, Netherlands.

In Weinberg’s study, the strongest association was linked to a variant of a gene called huntingtin, known for its role in causing Huntington’s disease. This condition results from repeating genetic sequences that prompt the production of faulty proteins. Conversely, the mutations associated with fibromyalgia are characterized by single-letter changes throughout the gene.

However, Bohr emphasizes that this mutation is unlikely to be the sole contributor to fibromyalgia. “It needs to be viewed alongside other risk factors and genetic elements.” There are likely thousands of contributing variants, along with external factors such as exposure to air pollution, she states. Larger studies are essential to uncover all contributing variants.

Despite certain limitations, the mutations identified by Weinberg’s team are found in genes linked to neuronal function, indicating that crucial mechanisms of fibromyalgia likely occur in the brain. Similarly, Gelernter’s research has highlighted variants previously connected to pain and neurologically related issues like post-traumatic stress disorder and depression.

These findings reaffirm a prevailing theory about fibromyalgia: “There’s a significant issue within the brain tissue,” said Bohr. Tracking these mutations may help identify key cell types, brain regions, and biochemical pathways that could become targets for future therapies. However, Bohr cautions that this is still years away unless existing drugs targeting known mechanisms prove relevant. Current treatments focus on approaches such as exercise, therapy, and antidepressants, though results are mixed.

Nevertheless, factors aside from genetics may also be influential. David Anderson and colleagues at King’s College London previously identified signs suggesting fibromyalgia may have autoimmune origins. In 2021, mice injected with antibodies from fibromyalgia patients exhibited symptoms like painful hypersensitivity and muscle weakness. Furthermore, research in September showed that these mice displayed atypical sensory responses, where nerves usually responsive to light touch began reacting to cold stimuli—mirroring the chronic pain experienced by fibromyalgia patients from non-painful stimuli, such as mildly lower temperatures.

“I firmly believe in the conclusions of our fibromyalgia research and anticipate that the findings will pivot the field’s focus toward autoantibodies [targeting the body’s tissues] and peripheral nerve cells [neurons outside of the brain and spinal cord], forming a new mechanism,” Anderson stated.

Bohr, however, points out that this recent research does not discount other theories. With rigorous statistical standards, while confident in the variants discovered and their implied mechanisms, they likely overlook many others. Gelernter and his team also detected several variants linked to autoimmune responses.

Professor Bohr characterizes this work as an essential “first step” towards understanding the roots of fibromyalgia. “What’s the pathway?” she inquires. “And is there something we can target?”