A massive global study links the chronic pain condition to 26 genes associated with brain signalling, marking a turning point in understanding its biological roots.
Researchers say they have identified the first genetic risk factors for fibromyalgia, offering compelling evidence that the chronic pain syndrome is fundamentally a disorder of the central nervous system.
The study, the largest of its kind, analysed genetic data from 11 international cohorts, including 54,629 individuals diagnosed with fibromyalgia and more than 2.5 million controls.
The researchers uncovered 26 genetic loci linked to fibromyalgia, providing the clearest biological basis yet for a condition long clouded by uncertainty and scepticism. Their findings are yet to be peer-reviewed by a journal but have been published as a pre-print on PubMed Central.
“This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities,” the researchers wrote.
The strongest genetic signal emerged from a variant in the HTT gene, which also causes Huntington’s disease when mutated. Another key player, GPR52, regulates HTT and is already being explored as a drug target for Huntington’s. Other implicated genes, including CAMKV, DCC, DRD2, MDGA2 and CELF4, have established roles in brain development, neuronal signalling and pain processing.
The results paint a picture of fibromyalgia as a brain-based disorder characterised by dysregulated neural communication rather than inflammation or peripheral tissue damage.
The researchers noted that the genetic underpinnings of fibromyalgia are shared with a remarkably wide variety of disease types. Besides brain-related traits, genetic correlations implicate the digestive, genitourinary and respiratory systems.
Additionally, certain risk loci overlapped with long covid (BPTF) and ME/CFS (OLFM4, RABGAP1L/GPR52), two poorly characterised disorders, albeit with different lead variants.
“These findings could point towards genetic factors associated with comorbidities and/or clinically misdiagnosed conditions,” the researchers wrote. “However, another plausible explanation of this widespread pleiotropy is that fibromyalgia genetics capture a core, transdiagnostic vulnerability.
“Such shared genetic architecture, rooted in central nervous system function, could predispose individuals to a spectrum of conditions characterized by sensory and/or affective dysregulation, which may manifest clinically as fibromyalgia, irritable bowel syndrome, post-traumatic stress disorder or a constellation of other disorders, depending on other genetic and environmental factors.”
The research team found that the heritability of fibromyalgia was exclusively enriched in brain tissues and neural cell types, particularly neurons involved in sensory processing. No enrichment was observed in immune or non-neural tissues, challenging theories that fibromyalgia is primarily an autoimmune or inflammatory disease.
This neural signature supports the concept of central sensitisation, a state of heightened nervous system sensitivity that amplifies pain perception and has long been proposed as a mechanism behind fibromyalgia.
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Despite the condition being two to three times more common in women, the study found virtually no genetic differences between sexes.
The genetic correlation between male and female fibromyalgia cases was nearly perfect, suggesting that environmental, hormonal, or psychosocial factors likely explain the higher prevalence in women rather than genetic predisposition.
The diagnostic criteria for fibromyalgia have changed over time, with the most widely used criteria, from the American College of Rheumatology, requiring widespread pain and tenderness across multiple body regions, alongside some combination of fatigue, difficulty with thinking or remembering, and waking up tired, all present at a similar level of severity for at least three months the researchers noted.
“Crucially, this definition removed the prior requirement for patients not to have another explanatory disorder, stating instead that ‘a diagnosis of fibromyalgia is valid irrespective of other diagnoses’,” they wrote.
“To date, there are no widely accepted biomarkers for fibromyalgia. Treatment often focuses on non-pharmacological treatments like exercise and behavioural interventions, since established pharmacotherapies such as tricyclic antidepressants, cyclobenzaprine, serotonin-norepinephrine reuptake inhibitors and gabapentinoids are usually only modestly effective [though emerging therapies like low-dose naltrexone, cannabinoids, ketamine and neurostimulation show promise].
“There is a significant unmet need for effective fibromyalgia therapeutics.”
The researchers said fibromyalgia’s genetic links extended far beyond pain, with the disorder showing strong genetic correlations with other chronic pain syndromes, psychiatric conditions, and somatic disorders.
The highest overlaps were observed with low back pain, post-traumatic stress disorder and irritable bowel syndrome, all with genetic correlations above 0.7.
A genetic correlation above 0.7 indicates a remarkably strong overlap, meaning fibromyalgia and these conditions share more than 70% of their genetic risk factors. In practical terms, people genetically predisposed to fibromyalgia are also highly likely to be predisposed to chronic back pain, PTSD and IBS. This suggests that these disorders may spring from shared biological roots within the brain and nervous system, rather than from separate or purely physical causes.
Significant connections were also seen with depression, anxiety, fatigue and sleep disturbances, reinforcing the notion that fibromyalgia shares biological roots with a broad spectrum of sensory and affective conditions.
Interestingly, fibromyalgia’s genetic relationships with autoimmune diseases such as rheumatoid arthritis and Sjögren’s syndrome were comparatively weak, although the researchers said these associations should be “interpreted with caution in light of the potential for diagnostic misclassification of fibromyalgia as Sjögren’s syndrome or RA”.
When they dissected subtypes, they found stronger correlations with the seronegative form of rheumatoid arthritis – typically less inflammatory and more heterogeneous – than with the classic seropositive type.
Similarly, fibromyalgia was more closely linked to T2-low asthma, a subtype lacking clear immune markers, than to T2-high asthma. These findings suggest that fibromyalgia may intersect genetically with less well-defined, system-wide syndromes that involve neural regulation rather than autoimmunity, they said.
The study also revealed striking pleiotropy, with fibromyalgia risk variants influencing a wide range of traits. Many were previously associated with pain sensitivity, insomnia, educational attainment, body mass index and depression. This broad genetic overlap may help explain the high comorbidity rates observed clinically and supported the idea of a shared central mechanism underlying diverse disorders of pain and perception.
Beyond its diagnostic implications, the study opened new therapeutic avenues. The identification of the HTT-GPR52 pathway and the CELF4 gene provides molecular targets for potential treatment development. GPR52 is already being investigated as a therapeutic target in neurodegenerative diseases, and CELF4-based gene therapies are being explored for chronic pain.
“These loci represent the first genetically supported molecular targets for fibromyalgia, providing tangible starting points for developing mechanism-based treatments,” the researchers wrote.
The acknowledged that their work had limitations. Case definitions relied on diagnostic codes from electronic health records, which may not perfectly capture all individuals meeting clinical criteria. Additionally, most participants were of European ancestry, meaning more diverse datasets would be needed to ensure the findings apply globally.
Nonetheless, the results represent a major step forward in understanding one of the most perplexing chronic pain conditions.
“In summary, our large-scale multi-ancestry GWAS provides a map of 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,” the researchers concluded.
“The identification of specific risk loci provides the field with concrete molecular starting points, enabling hypothesis-driven research to dissect the biological basis of its pathophysiology and its shared aetiology with comorbid conditions.”
