The genetic architecture of fibromyalgia across 2.5 million individuals, 2025, Kerrebijnet al.

[voner]

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.

The genetic architecture of fibromyalgia across 2.5 million individuals

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...

www.medrxiv.org

Preprint: MedRxiv | Open Access

 

[forestglip]

I see some familiar genes from DecodeME: RABGAP1L, OLFM4, DCC

 

[Utsikt]

The strongest association was with a coding variant in HTT , the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52

HTT is responsible for the production of Huntingtin (Htt), a protein that interacts with more than a hundred other proteins and is involved in functions like the transport of materials within cells, synaptic function, and protection of cells from self-destruction.

It’s only when the gene is mutated (too many CAG repeats) that it becomes a problem and creates mutated Huntingtin (mHtt). mHtt eventually leads to loss of neurons in a progressive and eventually fatal disease.

GPR52 is apparently involved in the chain of actions that results in mHtt causing neurons to die. Knocking out GPR52 in mice reduced symptoms and mHtt.

https://academic.oup.com/brain/article/141/6/1586/5003147

 

[forestglip]

I pulled up the top hits from this study and compared to DecodeME to look for those that are in the same general location as at least a somewhat significant locus in ME/CFS.

So these images are the results for ME/CFS, but with the top fibromyalgia SNPs marked as black triangles and with their ID to the left. Top hits for ME/CFS are purple diamonds. The p-values above the images are for fibromyalgia.

rs149109767
Nearest gene: HTT
p=2.2e-12


rs62100765
Nearest gene: DCC
p=1.5e-9


rs1443914
Nearest gene: OLFM4
p=2.1e-9


rs140473396
Nearest gene: CNNM2
p=2.2e-9


rs6657341
Nearest gene: RABGAP1L
p=7.1e-9


rs28645908
Nearest gene: FAM135B
p=2.3e-8


rs34683740
Nearest gene: RWDD3
p=4.3e-8


rs325506
Nearest gene: NUDT12
p=4.9e-8

 

[mariovitali]

...and one also gene of special interest is SRD5A2 which is 5 Alpha reductase type 2 , a gene targeted by a medication called Finasteride, the medication i took which could be responsible for my MECFS

 

[rvallee]

Looking at the list of authors, this is a huge study. I see something like 10 countries involved.

So first question I would ask is: why is this wrong/invalid? Or does it look legit? Are we finally seeing some science being done about this? Is medicine finally working to science the shit out of this?

 

[Yann04]

2.5 million cases. I thought decode ME was big

 

[forestglip]

2.5 million cases. I thought decode ME was big

Maybe you meant total participants, but in terms of cases it's around 54,000. Around 3 times more.

2,563,755 individuals (54,629 cases and 2,509,126 controls)

 

[Yann04]

Maybe you meant total participants, but in terms of cases it's around 54,000. Around 3 times more.

whats a difference between a participant and a case?

 

[forestglip]

whats a difference between a participant and a case?

Cases are the ones with fibromyalgia. Controls are healthy. And I meant participants as everyone combined.

 

[Yann04]

ahhh. so the title is kind of clickbait. as in 2.5 million people total. but 50k with fibro.

Kind of like if decode ME boasted about as many individuals as Uk biobank had

 

[ChronicallyOverIt]

...and one also gene of special interest is SRD5A2 which is 5 Alpha reductase type 2 , a gene targeted by a medication called Finasteride, the medication i took which could be responsible for my MECFS

You must be familiar with the work the PFS network is doing? They are doing WGS right now which would shed some light on this. I don’t think I’ve heard of many cases of PFS presenting as CFS, aka with PEM. Most PFS patients work out as therapy since nothing else works.

 

[ChronicallyOverIt]

Dang they used FLAMES instead of MAGMA. We need to use FLAMES somehow on the decode ME data

 

[SNT Gatchaman]

These findings establish a firm biological basis for a condition long defined solely by its clinical symptoms, and whose validity remains debated in some circles.

Headline, as with DecodeME

So first question I would ask is: why is this wrong/invalid?

I've only read through once. I note that they start out by framing fibromyalgia as central sensitisation, with a nod to other (minor/possible) contributions —

Fibromyalgia is considered the prototypical central sensitization or nociplastic pain syndrome. Central sensitization is a neuroplastic process by which the central nervous system becomes excessively sensitive to nociceptive input from the peripheral nervous system, leading to multisite hyperalgesia (an increased pain response to painful stimuli) and allodynia (a pain response to typically non-painful stimuli).

Central sensitization is a transdiagnostic contributor to chronic pain, and also occurs in conditions like rheumatoid arthritis and osteoarthritis that involve damage to peripheral tissues, although peripheral injury is not necessary to trigger it. […] Other biological processes that may play a role in at least a subset of fibromyalgia patients include (demyelinating) polyneuropathy, endocrine dysregulation, oxidative stress, and dysfunctional mitochondrial energy metabolism.

Is the analysis at risk of bias using this lens, looking for explanations with neural mechanisms and genes rather than non-neural possibilities?

HTT, the causal gene for Huntington’s disease (HD), is ubiquitously expressed and involved in diverse cellular processes including signaling, transcriptional regulation, cell division, endocytosis, autophagy, and axonal transport, and is required for healthy neurodevelopment.

We found a second association with a possible HD link: rs6657341-A (OR = 0.961, p = 7.1 × 10-9 ), an intronic variant in RABGAP1L, ~150 kilobases upstream of its second-nearest gene GPR52. RABGAP1L regulates RAB proteins, which direct intracellular trafficking, but has no clear link to fibromyalgia. Conversely, GPR52 is a brain-specific orphan G-protein coupled receptor being investigated as a drug target for HD as it regulates HTT levels.

STK31 encodes a testis-specific protein kinase with unclear relevance to fibromyalgia; however, the variant is ~400 kilobases upstream of NPY (its sixth-nearest gene), an abundant neuropeptide that modulates appetite, circadian rhythm, anxiety, cardiovascular function, and immune responses and has both pro- and anti-nociceptive effects.

ARHGAP15 which encodes a Rho GTPase-activating protein that regulates neutrophils and cellular functions such as cytoskeletal organization. In mouse models, ARHGAP15 knockout impairs cortical interneuron excitability (causing subclinical seizures) and hippocampal function (causing memory impairment). The variant is also ~450 kilobases downstream of KYNU (the third-nearest gene), which encodes kynureninase, an enzyme that cleaves kynurenine into anthranilic acid. Kynurenine and its metabolites are involved in pain processing

One particularly notable hit was rs2734833, an intronic variant in DRD2, a locus with pervasive psychiatric and sleep associations. DRD2 encodes the dopamine D2 receptor, which influences motivation and cognition and is the primary target of most antipsychotic drugs. In addition, DRD2 was one of the first loci discovered to modulate sleep duration. The variant lies ~150 kilobases downstream of NCAM1, the fourth-nearest gene, which encodes a cell surface receptor (also known as CD56) with both nervous and immune roles. In the nervous system, it regulates neural cell adhesion, neuronal migration, neurite outgrowth, axon guidance, and synaptic plasticity, and plays a role in memory. In the immune system, CD56 is the primary marker for natural killer (NK) cells and distinguishes their two main subtypes. It helps NK cells attach to target cells and trigger the release of cytotoxic granules that kill target cells.

BCL11A. Besides its canonical role in hematopoiesis and repression of fetal hemoglobin in adults, BCL11A has neurodevelopmental roles

BPTF, which encodes a subunit of the developmentally essential NURF chromatin remodeling complex. BPTF haploinsufficiency causes a neurodevelopmental disorder with […]. The lead variant at this locus is in strong LD (r 2 = 0.831) with the poorly characterized anti-apoptotic gene C17orf58.

NPC1 encodes a transmembrane protein vital for intracellular cholesterol trafficking, and biallelic loss of NPC1 function causes Niemann-Pick disease type C1, characterized by lysosomal lipid accumulation, neuroinflammation, abnormal dendrite growth, neurofibrillary tangles, and neuroaxonal dystrophy

And alongside neural vs non-neural, some discussion may be preferring neurodevelopmental mechanisms over other neural possibilities, eg myelin maintainance —

DCC encodes a transmembrane receptor that guides midline-crossing axons during neurodevelopment and regulates myelin structure and axon domain organization.

 

[forestglip]

HTT is responsible for the production of Huntingtin (Htt), a protein that interacts with more than a hundred other proteins and is involved in functions like the transport of materials within cells, synaptic function, and protection of cells from self-destruction.

It’s only when the gene is mutated (too many CAG repeats) that it becomes a problem and creates mutated Huntingtin (mHtt). mHtt eventually leads to loss of neurons in a progressive and eventually fatal disease.

GPR52 is apparently involved in the chain of actions that results in mHtt causing neurons to die. Knocking out GPR52 in mice reduced symptoms and mHtt.

https://academic.oup.com/brain/article/141/6/1586/5003147

More from the paper:

The linked associations of HTT and its regulator GPR52 highlight a clear repurposing opportunity, as GPR52 is already an investigational drug target for Huntington’s disease.

As the images I posted above show, there seem to be at least suggestive signals (p<5e-6) at these same two locations in DecodeME. So maybe GPR52 and HTT form an important pathway in ME/CFS as well.

Another drug target:

Furthermore, our identification of CELF4 as a fibromyalgia risk locus provides a direct genetic rationale for exploring CELF4-based gene therapies – already under investigation for chronic pain – for fibromyalgia in particular.

 

[ME/CFS Science Blog]

In contrast to DecodeME, most of the participants were recruited from other cohorts which used the ICD-code M79.7 to select fibromyalgia patients. They basically combined all the major databases (All of us, UK Biobank, FinnGenn, etc.). 87% of patients were female.



Most of the implicated genes pointed towards brain functions. The study also found strong genetic correlations with other pain conditions and neuropsychiatric conditions but much less so with autoimmune disorders. The authors argue that the data is consistent with the central sensitization model of fibromyalgia, in which the central nervous system develops heightened responsiveness to pain and other sensory stimuli.




Because there were so strong correlations with many other medical conditions, the authors caution that the fibromyalgia genetics they found might capture a core, transdiagnostic vulnerability to multiple conditions. In other words, they might not be very specific to fibromyalgia.

I was wondering if this might also apply to many of the ME/CFS hits. That except for pointing to neurons in the brain, they don't mean much specific.

 

[Jonathan Edwards]

I was wondering if this might also apply to many of the ME/CFS hits. That except for pointing to neurons in the brain, they don't mean much specific.

I suspect that in one sense that is going to be so, and expected, but I am not sure it makes things less important, or, in another sense, less specific.

Being female could be considered very nonspecific, affecting loads of diseases. But it could also be considered as highly specific - the effect of not having a Y chromosome (since both men and women use one or other X).

Being of Black African or Sephardi Jewish origin might similarly be considered very non-specific but the impact on disease can be tracked down to specific genes in at least some cases.

In inflammatory rheumatic disease we see genes that seem to confer risk across a broad front and others just for one disease. Both are equally important to understanding. Some are polymorphisms of cytokine receptors or regulators of clonal selection like PTPN22 that are very specific in their roles but provide risk across several diseases.

As for RA, it seems to me that ME/CFS, with a prevalence around 0.5%, and unpredictable occurrence on a background of everyone seeing much the same environmental factors and only a modest family co-occurrence, must involve one or more stochastic steps on a general predispositional background.

I worry about the sorts of cohorts they have collected together for fibromyalgia - partly because physicians differ by a factor of 100 as to how often they make the diagnosis! But the analysis may be reasonable. If we take central sensitisation simply to mean that peripheral stimuli cause more grief than expected for reasons to do with central nervous connections that seems to me a plausible analysis.

 

[V.R.T.]

If we take central sensitisation simply to mean that peripheral stimuli cause more grief than expected for reasons to do with central nervous connections that seems to me a plausible analysis.

The issue is that while your definition of the term here is reasonable and fits with theories of ME/CFS we have been discussing, the concept of 'central sensitisation' is intrinsically bound up with BPS psychobabble about people misinterpreting normal sensations and having false illness beliefs.

 

[Utsikt]

The issue is that while your analysis here is reasonable and fits with theories of ME/CFS we have been discussing, the concept of 'central sensitisation' is intrinsically bound up with BPS psychobabble about people misinterpreting normal sensations and having false illness beliefs.

Yeah, central sensitisation has a tendency to go from «neurons react more than they would normally» to «you react more than you should normally».

 

[ME/CFS Science Blog]

Another issue is that fibromyalgia is usually not about heightened pain sensitivity when there is peripheral input. It's about constant widespread pain even without any peripheral input. So rather than just have an increased response to pain stimuli when these arise, patients seem to have the pain switch constantly turned on.

So central sensitisation might not be the best term to describe this.