People with fibromyalgia experience systemic muscular and skeletal pain, fatigue, and poor sleep. Fibromyalgia often coincides with other conditions including myalgic encephalomyelitis/chronic fatigue syndrome, psychiatric disorders, and some autoimmune diseases. Although researchers suspect that fibromyalgia is strongly influenced by genetics, so far, scientists have not pinpointed responsible genes, complicating research into the disease and treatment options.
As a result of the unclear disease mechanism of fibromyalgia, Kevin Hackshaw, a rheumatologist at the University of Texas at Austin, said that some physicians don’t take the condition seriously. “I would say greater than 50 percent of patients that eventually come to us for treatment are really individuals who have experienced rejection from other physicians along the way, believing that fibromyalgia is not real, is made up…and is kind of a wastebasket term, and it is quote unquote ‘all in your head,’” he said.
Recently, a study led by an international team of researchers tackled the complexity of gene associations in fibromyalgia with a meta-analysis of several genome-wise association studies encompassing 2.5 million people. In a study published in Nature Medicine, the researchers presented 26 loci associated with fibromyalgia risk.1 The researchers also found strong associations with genes involved in nervous system function and pain processing.
“This tells us something about the biological basis of fibromyalgia and teaches us about chronic pain,” said Nasa Sinnott-Armstrong, a geneticist at the University of Washington looking at gene environment interactions and study coauthor.
The study started as a collaboration with Sinnott-Armstrong and colleagues they met as a graduate student at Stanford University: Michael Wainberg, a computational biologist at the University of Toronto who was also a graduate student at Stanford University, and Hanna Ollila, currently a genetic epidemiologist at the University of Helsinki who completed a postdoctoral position at Stanford University. Today, Wainberg uses statistics and modeling to study chronic pain and Ollila explores post-infectious diseases and sleep disorders.
Nasa Sinnott-Armstrong studies how environmental factors influence individual’s genetic risk for certain conditions.
Robert Hood, Fred Hutch Cancer Center
The trio reconnected after launching their respective careers because of the overlap between chronic pain and chronic fatigue conditions, forming the Chronic Pain Genomics Consortium. The team focused on fibromyalgia because, while previous studies pointed to genetic involvement, none had yet identified associated genes.2,3
The researchers combined 11 cohorts from international databases, which included more than 54,000 individuals with diagnosed fibromyalgia, into a meta-analysis to identify strongly associated genetic signatures with the condition. The researchers identified variants in 26 genetic loci associated with fibromyalgia. Considering the heterogeneity in fibromyalgia, Ollila said “I was very positively surprised how coherent all of the associations at the end were when we combined all of the data across the 11 cohorts.”
The variant with the strongest association with fibromyalgia was in HTT, the gene encoding the Huntingtin protein that is involved in several cellular processes and in proper neurodevelopment. While mutations in one exon of HTT cause Huntington’s disease, the variant in the present study is in a different region of the gene from the one associated with the disease.
Several other variants were also in or near genes involved in pain processing or nervous system function. “Those findings, of course, give like a very nice biological cues and clues about the disease mechanisms,” Ollila said.
In addition to working as an international team, the researchers also worked alongside an interdisciplinary group of experts that Ollila said helped extend their findings beyond an initial list of associated genes. For example, the team cross-referenced their 26 risk loci variants with other conditions available in the databank catalogues. They found that several of their identified variants also correlated to body mass index, type 2 diabetes, psychiatric conditions, as well as other pain-related diseases, metabolic disorders, and immune diseases.
Some researchers have previously suggested that fibromyalgia could be driven by an autoimmune mechanism as opposed to the nervous system.4,5 To explore this claim, the study authors evaluated the tissues and cell types that highly expressed genes where one of the identified variants was within it or with 100 kilobases of it. The majority of enriched genes came from the central nervous system.
Michael Wainberg uses computational models to study brain-related diseases.
Submitted by Michael Wainberg
“A common thread that’s woven through many parts of this analysis is that there are many pieces of evidence that are pointing towards fibromyalgia being a neurological condition rather than an immune condition,” Wainberg said.
Additionally, although the majority of fibromyalgia cases came from women, the researchers did not find and sex-specific difference in the presence of risk variants between males and females. Hackshaw, who wasn’t involved in the study, said that this could be due to nongenetic triggers influencing the development of fibromyalgia. The study researchers said that it could also indicate differences in diagnosis.
While Hackshaw said that the study was very strong because of its large sample population, he pointed out that the majority of the cohorts came from individuals of European descent. The researchers of the study also noted this, adding that it could limit the generalizability of the findings.
Overall, though, “This is really a really major validation paper for fibromyalgia,” said Hackshaw. “It establishes essential strong evidence that fibromyalgia has a measurable, biologic architecture, and it is focused on the nervous system.”
The researchers hope to use this study as a basis to investigate other chronic pain conditions. “Looking at this as one aspect of a broader set of important questions to understand about chronic pain will help us reach a point where better therapies, better treatments, better diagnoses are available,” Sinnott-Armstrong said.
- Kerrebijn I, et al. The genetic architecture of fibromyalgia across 2.5 million individuals. Nat Med. 2026.
- Arnold LM, et al. The fibromyalgia family study: A genome-wide linkage scan study. Arthritis Rheum. 2013;64(4):1122-1128.
- Zorina-Lichtenwalter K, et al. Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling. Pain. 2023;164(10):2239-2252.
- Goebel A, et al. The biology of symptom-based disorders – time to act. Autoimmun Rev. 2023;22(1):103218.
- Goebel A, et al. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021;131(13):e144201.
