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[Preprint]. 2025 Sep 19:2025.09.18.25335914.
doi: 10.1101/2025.09.18.25335914.

The genetic architecture of fibromyalgia across 2.5 million individuals

Isabel Kerrebijn  1   2 , Gyda Bjornsdottir  3 , Keon Arbabi  1   2   4 , Lea Urpa  5   6   7 , Hele Haapaniemi  7 , Gudmar Thorleifsson  3 , Lilja Stefansdottir  3 , Stephan Frangakis  8 , Jesse Valliere  5   7 , Lovemore Kunorozva  6   7   9   10 , Erik Abner  11 , Caleb Ji  1   12 , Bitten Aagaard  13 , Henning Bliddal  14 , Søren Brunak  15   16 , Mie T Bruun  17 , Maria Didriksen  18 , Christian Erikstrup  19   20 , Arni J Geirsson  21 , Daniel F Gudbjartsson  3 , Thomas F Hansen  22   23   24 , Ingileif Jonsdottir  3 , Stacey Knight  25 , Kirk U Knowlton  25 , Christina Mikkelsen  18 , Lincoln D Nadauld  26 , Thorunn A Olafsdottir  3   27 , Sisse R Ostrowski  18   28 , Ole Bv Pedersen  28   29 , Saedis Saevarsdottir  3   27 , Astros T Skuladottir  3   27 , Erik Sørensen  18 , Hreinn Stefansson  3 , Patrick Sulem  3 , Olafur A Sveinsson  27   30 , Gudny E Thorlacius  3 , Unnur Thorsteinsdottir  3 , Henrik Ullum  31 , Arnor Vikingsson  21 , Thomas M Werge  28   32 ; Chronic Pain Genomics Consortium; FinnGen; DBDS Genomic Consortium; Estonian Biobank Research Team; Genes & Health Research Team; Richa Saxena  6   9   10   33 , Kari Stefansson  3 , Chad M Brummett  34   35   36 , Bente Glintborg  28   37 , Daniel J Clauw  38 , Thorgeir E Thorgeirsson  3 , Frances Mk Williams  39 , Nasa Sinnott-Armstrong  40   41   42   43 , Hanna M Ollila  6   7   9   33 , Michael Wainberg  1   2   12   44   45
Affiliations

The genetic architecture of fibromyalgia across 2.5 million individuals

Isabel Kerrebijn et al. medRxiv. .

Abstract

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct 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, identifying the first 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including CAMKV, DCC, DRD2/NCAM1, MDGA2, and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. 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. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. 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.

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Conflict of interest statement

CMB is a consultant for Vertex Pharmaceuticals and Merck Pharmaceuticals providing expert medicolegal testimony. SF is a consultant for Vertex Pharmaceuticals. BG has received research grants (paid to institution) from Sandoz, AbbVie, AlfaSigma, and Eli Lilly. SB has ownership interests in Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, and Eli Lilly and Co. CE has received unrestricted research grants from Novo Nordisk and Abbott Diagnostics (administered by Aarhus University Hospital, no personal fees received). GB, TET, GET, TAO, SS, HS, IJ, ATS, GT, LS, UT, PS, and DFG are employees of Amgen deCODE Genetics.

Figures

Figure 1:
Figure 1:. Study overview.
“Copenhagen Hospital Biobank” is short for “Copenhagen Hospital Biobank and Danish Blood Donor Study”.
Figure 2:
Figure 2:. Manhattan plot of the primary meta-analysis.
Gold-highlighted variants have linkage disequilibrium r2 > 0.001 and are within 5 megabases of the lead variants (diamonds). The nearest gene to each lead variant is labeled.
Figure 3:
Figure 3:. Phenome-wide associations of lead variants.
Each of the 26 lead variants from the primary meta-analysis was tested for overlap with genome-wide significant variants from the GWAS Catalog, either with the lead variant itself or variants with r2 > 0.8 (top). The 26 lead variants were also tested for association with 330 diseases in a meta-analysis of the Million Veteran Program, FinnGen and the UK Biobank (middle), and 124 drug classes in FinnGen (bottom), applying Bonferroni correction across the number of variants and diseases/drug classes tested. The number of variants (out of 26) significantly associated with each disease or drug is listed in brackets; for brevity, only diseases or drugs associated with at least 10% of the lead variants (i.e. ≥3 of 26) are shown, or 15% (i.e. ≥4 of 26) for the GWAS Catalog analysis, with full results listed in Table S4–S6. Only lead variants with at least one significant phenome-wide association are shown.
Figure 4:
Figure 4:. Tissue and cell-type enrichments.
Fibromyalgia heritability enrichments among variants inside or within 100 kilobases of genes with enriched expression in a) tissues in the Genotype-Tissue Expression (GTEx) project, and b) cell types in PanSci, a ~20 million whole-mouse single-cell atlas. Results are shown as negative log p-values for enrichment, grouped and colored by tissue group (GTEx) or cell lineage (PanSci), with random side-to-side jitter for visibility. Bonferroni-significant tissues and cell types are labeled. Full results are listed in Table S7–S9.
Figure 5:
Figure 5:. Genetic correlations between fibromyalgia and FinnGen disease endpoints.
a) Genetic correlations of the 337 disease endpoints with Bonferroni-significant genetic correlations with fibromyalgia, grouped by disease area. The area of each circle is proportional to the logarithm of its genetic correlation p-value. b) Genetic correlations of the 18 diseases with genetic correlation greater than 0.7; error bars denote 95% confidence intervals. Full results are listed in Table S10.
See this image and copyright information in PMC

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