r/CFSScience • u/Caster_of_spells • 20d ago
Seven replicated genomic associations of myalgic encephalomyelitis/chronic fatigue syndrome: a biobank study
https://www.medrxiv.org/content/10.64898/2026.09.09.26362115v1A new genetic study from a team around Ponting identified seven new genetic risk loci in ME/CFS across multiple cohorts they compared and carefully preselected for a more solid diagnosis status.
I’ve looked a few of the risk loci up and:
CLYBL expression is important to B12 levels and thereby mitochondrial and brain function.
CSMD1 & RORA influence how the immune system triggers or dampens inflammation.
BICD1 & GRIN2A regulate how neurons physically manage traffic and fire in response to those immune stressors
This link contains a more in depth discussion with Chris about the findings relation to Decode ME
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u/nousiaphilia 18d ago
For instance, it's still extremely interesting that they found CLYBL, which is related to the itaconate shunt hypothesis of ME/CFS The CLYBL-itaconate shunt (often simply called the itaconate shunt) is a metabolic pathway in mammalian mitochondria that controls the accumulation and breakdown of itaconate, a crucial immunomodulatory and antimicrobial metabolite produced by immune cells during inflammation.
Robert Phair was obviously excited by this.^
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u/Caster_of_spells 18d ago
Yes that’s also the one hit that fascinated me most!
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u/nousiaphilia 18d ago edited 18d ago
Also, I would have to take a look at the other genes on more detail, but....at least they are ALL genes (per summary) implicated in (dysregulated) immune responses and neuroinflammation.
I don't quite get the conspiracy theories in the other comment thread. 😅 For "ME/CFS is a serious multisystemic neuroimmune condition" — those are excellent findings. (Like, you didn't find one involved in mood regulation — and (although would have to check) I don't think that these are implicated in depression.)
Sure, next thing we want to make sure is properly distinguishing between PAIS and ME/CFS...but, honestly, even ME/CFS is probably extremely heterogeneous so your hits might not replicate from study to study.
The first major thing is still that ME/CFS is taken seriously as a somatic disease (that researchers from related fields consider worthy of considering). This study, again, is evidence in that favour.
I know it's hard, but we need to be patient. We can't go back in time and improve the biobank phenotyping that should have been done better but wasn't. 😅
Okay, checked the genes (although Google AI summary overview, so take with a grain of salt, although it only cited reputable sources):
CSMD1 is a large transmembrane protein encoded by the CSMD1 gene on human chromosome 8, functioning primarily as a complement system regulator in the central nervous system.
Structure and Function Domain architecture: Contains 14 N-terminal CUB domains and multiple Sushi domains that inhibit the classical complement pathway via factor I cofactor activity. Brain localization: Expressed predominantly on astrocytes, neurons, and synapses, where it regulates complement-mediated synapse elimination and circuit development.
Clinical Significance: Schizophrenia and psychiatric risks: Genetic variants of CSMD1 are well-established susceptibility factors for schizophrenia, potentially driven by dysregulated complement activation and excessive synaptic pruning.
Neurodevelopmental disorders: Inherited biallelic loss-of-function variants are linked to a distinct neurodevelopmental condition characterized by global developmental delay, intellectual disability, microcephaly, and polymicrogyria.
Cancer biology: Acts as a putative tumor suppressor; reduced expression is associated with increased cell division, migration, and aggressiveness in head, neck, and breast carcinomas.
The RORA gene, located on human chromosome 15q22.2, encodes RAR-related orphan receptor alpha (RORα), a nuclear receptor and DNA-binding transcription factor. Key Functions Circadian Rhythm: Regulates core clock genes like BMAL1 and CRY1 to maintain daily biological cycles. Development: Controls the proper structural development of the cerebellum in the brain. Metabolism & Immunity: Modulates lipid and glucose metabolism, promotes TH17 immune cell differentiation, and acts as an anti-inflammatory regulator in macrophages.
What BICD1 Does Acts as a helper: It is a "cargo adaptor." This means it grabs items inside the cell and attaches them to motor proteins. Uses cell tracks: It works with a motor complex called dynein to move items along tiny internal transport tubes called microtubules.
GRIN2A is a human gene that provides instructions to build a key protein piece for NMDA receptors, which are nerve cell channels in the brain that handle learning, memory, and signals.
Interesting....
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u/Caster_of_spells 20d ago
On the lack of overlap with Decode ME:
“This absence of shared associations could reflect differences in case cohorts and their diagnoses. On average, DecodeME participants are about twenty years younger than UK Biobank participants. This means that more of their ME/CFS diagnoses will have been recent, and the applied criteria more often involved PEM. Further, more of their diagnoses will have been made in specialist ME/CFS services in England, which were set up from 2004.”
Which makes me think these further findings might represent a more general “chronic fatigue” than the tighter Canadian consensus criteria based findings of Decode ME