Genetic Study of Fibromyalgia Points to Neurological Basis

An international team of researchers has identified multiple new genetic risk factors associated with fibromyalgia, a syndrome characterized by widespread pain and tenderness, fatigue, and problems with sleep, memory and mood.

The team analyzed genetic data from more than 2.5 million adults, of which 55,000 were fibromyalgia patients. They identified DNA sequence variants in 26 regions of the genome that affect the risk of developing fibromyalgia. Many of the genes implicated in these regions are involved in brain and nerve function.

The results provide the strongest evidence yet that fibromyalgia is primarily a nervous system disorder rather than an autoimmune disease, as has long been debated. “This work changes how we think about fibromyalgia at a fundamental level,” said Michael Wainberg, PhD, an investigator at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health, and the University of Toronto. “For decades, patients have been dismissed or told their pain is simply psychological. Our findings confirm the condition has a clear biological basis.”

Weinberg is co-senior author of the researchers’ published paper in Nature Medicine, titled “The genetic architecture of fibromyalgia across 2.5 million individuals,” in which they concluded, “This study provides robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.”

Fibromyalgia is a multifaceted syndrome that can encompass chronic widespread musculoskeletal pain, fatigue, sleep issues, cognitive impairment, and somatic symptoms, the authors stated. Fibromyalgia also commonly co-occurs with other pain conditions, including irritable bowel syndrome, chronic fatigue syndrome, autoimmune and neuropsychiatric disorders, and metabolic syndrome. Despite affecting about two percent of the global population, its existence has been debated, largely because its biological causes have remained unclear. “Whether fibromyalgia has an autoimmune component is a matter of long-standing debate,” the authors added.

Bringing together data from 11 health research studies from the U.S., U.K., Finland, Estonia, Denmark, and Iceland and 53 researchers across seven countries, the newly reported study was jointly led by Weinberg and collaborators at Fred Hutch Cancer Center and University of Washington in Seattle, and at the University of Helsinki in Finland and Massachusetts General Hospital in Boston.

The team conducted a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts. They scanned millions of genetic differences of individuals with and without fibromyalgia to find changes that were more common in those with the condition. Their results identified DNA sequence variants in 26 regions of the genome that affect the risk of developing fibromyalgia. Many of the genes implicated in these regions are involved in brain and nerve function. The variant most strongly linked to fibromyalgia risk was a coding variant within the HTT gene. Other mutations in this gene cause Huntington’s disease (HD), a severe, progressive and fatal neurodegenerative disorder.

Another variant pointed to a receptor called GPR52 that regulates HTT levels. This receptor is already being investigated as a possible drug target in Huntington’s disease. “Our strongest association (~9% increased risk of fibromyalgia) was with a common coding variant in HTT, the causal gene for HD, although this variant is distinct from the rare repeat expansion that causes HD,” the investigators wrote. “The variant results in the deletion of a single glutamic acid residue in the HTT protein. We also observe an association near GPR52, a regulator of HTT.”

By integrating their findings with a massive dataset of 20 million cells from various tissues, the researchers found further evidence for a neurological origin of fibromyalgia. Genes near fibromyalgia genetic risk factors were more active in nervous system cells than in other types of cells, which sets fibromyalgia apart from classical autoimmune conditions.  “Overall, our results suggest that fibromyalgia is not primarily an autoimmune disorder, although it may nonetheless have a peripheral immune and/or neuroimmune component,” they stated. “Power to detect this may have been limited by the predominantly European composition of our sample and by healthy participant bias in biobank cohorts.”

The study also revealed substantial genetic overlap between fibromyalgia and a range of other conditions, including low back pain, irritable bowel syndrome, and post-traumatic stress disorder. “Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome,” the scientists stated.

They think that shared biological mechanisms within the nervous system may make people susceptible to several of these conditions, explaining why they often appear together. “We know that chronic pain syndromes cluster together in individuals and families and are genetically similar,” said co-author Frances Williams, PhD, a rheumatologist at TwinsUK, King’s College London. “Targeting the shared mechanisms underlying them could potentially benefit a whole cluster of disorders.”

Even so, the study found that genetics is not the main determinant of whether someone develops fibromyalgia. The authors suspect that even people carrying many fibromyalgia genetic variants likely require another risk factor, such as a painful arthritic condition, to trigger fibromyalgia syndrome. “Understanding how genes, environmental exposures, and life events jointly contribute to risk of fibromyalgia syndrome is critical,” said co-senior author Nasa Sinnott-Armstrong, PhD, assistant professor at Fred Hutch Cancer Center. “Further research into triggers of fibromyalgia and corresponding changes to neural tissues will help understand what drives fibromyalgia and how to treat it.”

Despite fibromyalgia being diagnosed roughly three times more often in women than in men, the researchers did not find any genetic differences in risk between the sexes. This suggests that the higher prevalence in women could be driven by non-genetic factors, such as hormonal or environmental, or differences in pain sensitivity and diagnostic patterns.

The findings do not mean that fibromyalgia can now be diagnosed with a genetic test, nor do they immediately lead to a new treatment. However, they provide important new starting points for understanding the biology of fibromyalgia that will help guide future research into better diagnosis and treatment.

Williams added, “This study provides important new insights into why some people develop fibromyalgia syndrome and identifies biological pathways that could lead to new treatment approaches. One of these pathways is already the focus of drug trials for Huntington’s disease, raising the possibility that existing pharmaceutical research could eventually benefit people with fibromyalgia. The findings also help us better understand why fibromyalgia so often occurs alongside conditions such as anxiety and depression, bringing us closer to understanding the condition as a whole.”

In summary, the team stated, “Our study maps the genetic architecture of fibromyalgia, identifying 26 risk loci and providing robust genetic validation of the notion that fibromyalgia is primarily a central nervous system disorder. Identifying specific risk loci provides the field with concrete molecular starting points, enabling hypothesis-driven studies of pathophysiology and shared etiology with comorbid conditions.”

The study’s researchers have founded the Chronic Pain Genomics Consortium (https://paingenomics.org) to investigate other chronic pain syndromes, starting with pelvic pain. The consortium sees fibromyalgia as only the beginning of a broader exploration of the landscape of chronic pain conditions.

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