Preprint Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration

I like the writing style of this paper. When I read through the whole thing, it struck me as very comprehensible considering the subject matter. Unfortunately, a lot of scientific papers are extremely dense and you can only understand them if you're an expert in that tiny field. But Ponting's team did a good job making it accessible. Doctors and scientists from different fields will understand it easily. That's what science should be. It's useless if only your tiny clique can understand it.
 
I'd be really interested in a follow up of the brain enrichment by looking at enrichment in specific brain cell types. The brain finding is interesting, but hard to know what to do with it since the brain is a big place.

The following studies show examples of looking at specific cell-type expression. I'm pretty sure I even saw a study that looked at enrichment based on gene expression at different stages of development (embryo, fetus, etc), though I can't find it now.



A GWAS of tic disorders saw enrichment in brain tissue, then followed up by looking at specific brain cells (though they say they were underpowered with ~10,000 cases to reach any significant cell types using MAGMA):

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However, 4 brain tissues (putamen, caudate, nucleus accumbens, and frontal cortex Brodmann area 9) were significant in 1 test type [MAGMA] (Figure S1). This justified follow-up analysis of 39 broad brain cell types, which revealed 4 broad cell types (di- and mesencephalon inhibitory neurons, telencephalon projecting excitatory neurons, hindbrain neurons, and telencephalon projecting inhibitory neurons) that were significant in 1 test type [LDSC] (Figure S1).

A GWAS of panic disorder looked at enrichment in cell types throughout the body:
The single-cell analyses provided compelling evidence for the role of the CNS with limbic system (FDR=3.8×10-6), granule (FDR=4.0×10-5), purkinje (FDR=4.4×10-5), excitatory (FDR=4.4×10-5) and inhibitory (FDR=4.4×10-5, 1.5×10-5) neurons of cerebellum and cerebrum being implicated (Fig 2). We also found significant enrichment for visceral afferent neurons in the lung (FDR=8.2×10-4), heart (FDR=3.1×10-4), and eye, including retina amacrine (FDR=4.4×10-5) and ganglion cells (FDR=4.4×10-5). Our analysis of the foetal developmental gene expression atlas also implicated glial cell types, notably cerebrum astrocytes (FDR=1.7×10-3) (Fig 3).

A GWAS of Alzheimer's found MAGMA enrichment in the spleen. They followed up with individual cell types (though with a non-MAGMA method, I think) and found enrichment in microglia:
MAGMA tissue specificity analysis15 identified spleen (Pbonferroni=0.034) as the GTEx tissue where expression of the significant MAGMA genes was enriched (Supplementary Figure 2, Supplementary Table 3). Spleen was also significant in the previous MAGMA tissue specificity analysis performed in Jansen et al. (2019)8 and is a known contributor to immune function. To investigate enrichment at the cell type level, FUMA cell type analysis16 was performed with a collection of cell types in mouse brain, human brain, and human blood tissue, resulting in 6 single-cell (scRNA-seq) datasets significantly associated, after multiple testing correction (P<5.39×10−5), with the expression of LOAD-associated genes (Supplementary Figure 4, Supplementary Table 4). The only significant cell type in all six independent scRNA datasets was microglia.

A GWAS of nasopharyngeal carcinoma found CD8 T cells through cell-type specific MAGMA enrichment.
We found that NPC susceptibility was significantly associated with T and NK cells (P = 0.015 for MAGMA and P = 0.045 for RolyPoly; Fig. 2c, Additional file 2: Table S6). Analysis of the cell subtypes identified three suggestively enriched CD8+ T cell populations including cytotoxic CD8+ T cells, exhausted CD8+ T cells, and CD8+ T cells with high expression of interferon-induced genes (Fig. 2c, Additional file 2: Table S6).

A GWAS of hearing loss found enrichment in cell types of the cochlea. Notably, since GTEx doesn't contain expression data for this part of the body, they used mouse expression data.
To show evidence connecting hearing loss GWASs to cell type, we used two different methods accounting for gene size and linkage disequilibrium: LDSC,40 assessing the enrichment of the common SNP heritability of hearing loss in the most cell-type-specific genes and MAGMA,20 evaluating whether gene-level genetic association with hearing loss linearly increases with cell-type expression specificity. [...] When assessing the enrichment in SGN and cells from the cochlear lateral wall (stria vascularis), LDSC analysis revealed the involvement of spindle cells of the stria vascularis and root cells of the outer sulcus, whereas MAGMA analysis highlighted the involvement of basal cells of the stria vascularis in hearing loss (Figure 2D, Table S13).
 
Is there any way to find out if one's sample was actually used? Will general results be made available as to deviation among those with morbidities from ME exclusives?
 
Has data on comorbidities in the ME/CFS patients in the DecodeME patients been released? The protocol says that exclusion criteria are "(ii) any alternative diagnoses including major psychiatric illness (e.g. bipolar disorder or schizophrenia) that can result in chronic fatigue, as explicit in the Canadian Consensus and IOM/NAM criteria[4, 14]." so in my head that would include Hashimotos, Graves, Lupus, MS, Sjögrens etc. So quite a few B-cell autoimmune diseases that have HLA link if I'm not mistaking. If I remember correctly it wasn't possible to exclude such people in the control sample? Should it then not be possible that DecodeME spits up some HLA links because these illnesses are now underrepresented or am I overestimating their possible impact given their relatively low prevalence in the general population?

Would this possibly be an issue for the Precision Life combinatorial analysis if you have HLA genes that are somehow "close to each other"?
 
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