Large Study Describes Genetic Underpinning of Fibromyalgia

TOPLINEA genome-wide association study (GWAS) meta-analysis of fibromyalgia cases and control individuals identified 26 genetic risk loci for fibromyalgia, with the strongest association observed with a coding variant in the Huntingtin (HTT) gene. Fibromyalgia heritability was enriched within brain tissues and neural cell types, with genetic correlations with pain and musculoskeletal disorders, autoimmune disorders, and mental and behavioral disorders.METHODOLOGYResearchers performed multi-ancestry GWAS meta-analyses of fibromyalgia across 11 cohorts from multiple countries. The study included more than 2.5 million individuals, comprising 54,629 people with fibromyalgia (90% of European ancestry) and 2,509,126 control individuals.They identified fibromyalgia cases from inpatient and/or primary care records using diagnostic codes.Quality control and GWAS were performed for each cohort-ancestry pair, with inflation corrected using linkage disequilibrium score regression intercepts. A fixed-effects inverse variance-weighted meta-analysis was then conducted across cohorts and ancestries.A combined analysis was performed to identify genetic risk loci, prioritize causal genes through literature reviews and machine learning methods, and map heritability-enriched tissues and cell types.The primary meta-analysis identified 26 genome-wide significant (P < 5 × 10-8) risk loci for fibromyalgia; secondary meta-analyses included leave-one-cohort-out analyses, European-only meta-analyses, and sex-stratified meta-analyses.TAKEAWAYAmong the 26 lead variants identified, the most significant association was with rs149109767-A, an in-frame glutamic acid deletion in HTT (the causal gene for Huntington disease), with carriers showing approximately a 9% increased odds of fibromyalgia (odds ratio [OR], 1.09; P = 2.2 × 10-12).Across the 330 diseases and 26 variants tested, a phenome-wide association study identified 20 diseases associated with three or more lead variants after Bonferroni correction. These diseases fell into three categories: pain and pain-associated traits (dorsalgia, spondylosis, limb pain, joint pain, spinal stenosis, and cervicalgia), metabolic syndrome and comorbidities (type 2 diabetes, obesity, sleep apnea, coronary heart disease, hypertension, gout, lipoprotein/lipid disorders, cholelithiasis, and hypercholesterolemia), and immune diseases (autoimmune hypothyroidism, and asthma).Assessment of genes with enriched expression across 53 tissues showed heritability enrichment exclusively in brain regions (cortex, caudate, frontal cortex, putamen, and anterior cingulate cortex) and neuronal cell types, with the strongest cell-type association in dentate gyrus neurons (P = 1.3 × 10-6).Genetic overlaps were strongest with pain and musculoskeletal disorders, including conditions such as cervicobrachial syndrome (P = 9.2 × 10-65), myalgia (P = 9.4 × 10-45), hypermobility syndrome (P = 8.4 × 10-13), joint pain (P = 1.7 × 10-160), and low back pain (P = 1.1 × 10-137), and modest genetic correlations were observed with autoimmune disorders, including psoriatic arthropathies (P = 5.4 × 10-17), Sjögren disease (P = 1.7 × 10-6), rheumatoid arthritis (P = 3.1 × 10-16), and autoimmune hypothyroidism (P = 4.2 × 10-17).Fibromyalgia also showed genetic correlations with mental and behavioral disorders, including posttraumatic stress disorder (P = 6.6 × 10-16) and other commonly co-occurring conditions such as irritable bowel syndrome (P = 2.1 × 10-35).IN PRACTICE“[The study] findings establish a firm biological basis for a long-debated condition,” the authors of the study wrote, further adding that the results “suggest fibromyalgia is not primarily an autoimmune disorder, though it may nonetheless have a peripheral immune and/or neuroimmune component.”“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,” Professor Frances Williams, co-senior author of the paper, said in a news release.SOURCEThe study was led by Isabel Kerrebijn, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. It was published online on July 28, 2026, in Nature Medicine.LIMITATIONSThe cohort was primarily European, limiting the generalizability of the findings. Reliance on diagnostic codes could mean that individuals not meeting full syndromic criteria for fibromyalgia may have been included or that undiagnosed cases may have been excluded.DISCLOSURESCanadian contributions received support from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada Undergraduate Student Research Awards. In the US, support was provided by the Michigan Genomics Initiative and AI & Digital Innovation at the University of Michigan, Ann Arbor, Michigan, as well as through National Institutes of Health funding to authors and a generous donation. In Denmark, the Copenhagen Hospital Biobank received support from the Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; grants from the Novo Nordisk Foundation; and the Rigshospitalet Research Council Framework grant. The Danish Blood Donor Study received funding from Bio- and Genome Bank Denmark, the Danish Administrative Regions, the Danish Council for Independent Research, and the Novo Nordisk Foundation. The Parker Institute is supported by a core grant from the Oak Foundation. Further support in Denmark was received from the Novo Nordisk Foundation. In the UK, support was provided to an author by Versus Arthritis. In Iceland, support was provided by the European Commission to the PainFACT project, and in Estonia, support was provided by the EU through Horizon Europe research and innovation programs and Estonian Research Council grants. Some authors disclosed serving as a consultant, receiving research grants, or having ownership interests in various pharmaceutical companies; 13 authors disclosed employment with deCODE Genetics, a wholly owned subsidiary of Amgen.This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.