Study Cohort: 15,579 people with doctor-diagnosed ME/CFS + 259,909 UK Biobank controls (no ME/CFS). 85 % were women, average age ≈ 52 y.

How much is genetic? Common SNPs explain = 9.5 % of overall ME/CFS risk (heritability on the liability scale).     For comparison: - asthma = 10 % - arthritis = 12 % - type 2 diabetes = 13%     So ME/CFS is typical for complex diseases when you look only at common variants.

Key finding: 8 DNA regions change risk a little (odds-ratios ~1.08 ↑ or 0.93 ↓). OR 1.08 = 8 % higher odds of developing ME OR 0.93 = 7 % lower odds of developing ME Multiple genes stack up to increase or lower risk.

Main genes & plain meanings: - RABGAP1L (helps cells expel germs) - BTN2A2 (activates a special T-cell) - FBXL4 (keeps mitochondria healthy [energy]) - SUDS3 (controls brain immune cells)

- OLFM4 (tones down neutrophil bug-killing) - CCPG1 (cleans stressed ER parts) - CA10 (shapes nerve-to-nerve contacts) - ARFGEF2 / CSE1L (manage TNF-α, an inflammation signal)

Where do these genes matter most? A tool called MAGMA (it groups DNA signals by gene and checks which tissues use those genes) shows they’re used most in the brain. So the genetic clues link ME/CFS to the nervous system as well as the immune system.

Does infection matter? Yes. In people whose illness began after an infection, the OLFM4 signal is much stronger; it’s absent in non-infection cases.

Male vs female DNA effects? Variants act equally in men and women; male-only analysis lacked power but key female hits (CA10, ARFGEF2) still showed the same direction.

Immune insights: HLA allele DQA1*05:01 was slightly protective (less common in patients). HLA genes help immune cells recognise threats.

Overlap with other diseases? - The CA10 region is shared with multisite chronic pain (high probability it’s the same causal SNP). - None of the eight regions share causal SNPs with depression or anxiety studies.

So will this help identify treatments? When a disease-linked gene pinpoints a process (e.g., TNF-α release or mitochondrial upkeep) drug projects aimed at that process have higher success rate of projects without genetic support.

Example 1 - Inflammation angle DecodeME noted a region with the genes ARFGEF2 / CSE1L that regulate how cells package and release TNF-α, a key inflammatory signal. Existing anti-TNF drugs (used in rheumatoid arthritis & Crohn’s) could now be tested for ME/CFS.

Example 2 - Nerve-signalling angle Another hit, CA10, shares the same causal variant with multisite chronic pain. CA10 affects how nerve cells talk to each other. Compounds that fine-tune this synaptic pathway (already explored for pain) are now candidates to check in ME/CFS.

Will we be able to expand on insights with our new @amaticahealth RNA seq test? If a person carries a “risk” or “protective” version of immune-expressed genes like RABGAP1L, BTN2A2, OLFM4, ARFGEF2, CSE1L we can see if their RNA level go up or down.

This allows us to see how the generic variant is impacting the functioning of the system.

Example: If a risk DNA drops RABGAP1L RNA (weaker bug-clearing) or boosts OLFM4 RNA (stronger neutrophil brake), the up/down shift shows whether that variant turns immune defences down or inflammation up

More information on RNA-seq and the rest: https://amaticahealth.com/me-c...

So overall very much what we expected from the study. Risk factor genes that relate to immune system, mitochondria, and nervous system function. The necessary next steps now are to determine if these alterations cause functional changes that can drive the disease.

Or are they simply just a ‘trigger’ risk. I will come back to the Decode ME findings in a few months when we have our RNA data to see if we can confirm any changes in gene expression within these similar systems (TNF-a signalling etc) And track against disease profile.

I will also do some more breakdowns on the exact genes and their prevalence in other diseases, if known, over the next few weeks.

Study pre print link: https://www.pure.ed.ac.uk/ws/p...

@JackHadfield14 Jack: non-geneticist here fully anticipating this to be a stupid question, but when is genomic evidence treated primarily with drug projects aimed at the resulting process vs treatment with gene-therapy directly? Thanks

@James6939710330 These findings wouldn’t lead to genetic therapy. You’d need a main gene driver in the majority if not all patients to pursue that route. Sickle cell disease is an example of a disease that has been cured by gene therapy, it has a point mutation in the HBB gene in the majority of

@JackHadfield14 Thanks for all these explanations. As you know there are suicides announced weekly. How long before significant therapy. And do you think damage is irreversible in long term pts? Thank you

@TWestphalia I don’t think irreversible no. Therapy timeline, I think there will be repurposed therapeutics through precision diagnostics using methods like ourselves at @amaticahealth before you get research that progresses from these findings. I think we’ll have our first insights into

@JackHadfield14 Mais est-ce que cette etude est vraiment importante ?

@32Sfc46582 It’s validation of biological underlyings. We’ll get some more functional insights with the RNA I think. It’s a needed step in research to validate the immune and neuro roll as well.

@JackHadfield14 Great breakdown Jack and this is indeed a very significant milestone in my opinion. It lends even more credence to the suspected areas and will hopefully accelerate targeted research. Bring us a little bit more hope. 🙏🏻

@JackHadfield14 The findings from DecodeME are indeed significant, highlighting the intricate connections between immune response, mitochondrial function, and neural signaling in ME/CFS.

@JackHadfield14 Jack, @scott_scientist writes: I used to love genetics; I spent 8 years working in that field. Now it’s become a tool for averting responsibility for mass poisoning of our population. Researchers have access to billions of point mutations they can use to point blame on,/1

@JackHadfield14 Since @DecodeMEstudy has publicly released only 8 of the top genes so far, but mentioned 29 in total, how can we talk to the person doing our whole genome sequencing to focus on the ones not published? Or are they in the study somewhere? 1/n

@JackHadfield14 @threadreaderapp Please unroll

@JackHadfield14 In ‘CCPG1 (cleans stressed ER parts)’, what does ER stand for? Great summary thx!