Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of [ME/CFS], 2026, Maccallini et al
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Jonathan Edwards
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Is he the 'citizen scientist' Chris P referred to?
Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Maccallini, Paolo
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of poorly understood etiology.
We performed a meta-analysis of two European-ancestry ME/CFS genome-wide association studies (GWAS) with no overlap in subjects, DecodeME and Million Veteran Program, comprising a total of 19,470 cases and 699,111 controls. Post-GWAS analyses investigated the association between ME/CFS and specific tissues, cell types, cellular components, and canonical pathways. Findings were independently evaluated for replication against a module of ME/CFS risk genes previously prioritized by machine learning applied to rare coding variants from whole-genome sequencing (WGS) of ME/CFS cases and controls of European ancestry.
Tissue enrichment analysis implicated multiple brain regions and the pituitary, with no peripheral tissue reaching significance, and three survived Bonferroni-corrected replication. Gene-set analysis identified multiple neuronal and synaptic gene sets, several of which were independently replicated, with glutamatergic synapses as the most specific replicated signal. Cell-type analysis identified independent replicated signals in distinct neuronal populations of subcortical and cerebellar regions.
These results suggest a role for synaptic function in specific brain regions in the pathogenesis of ME/CFS, with convergent support from both common and rare variant data. Larger studies are needed to confirm these findings and to identify specific targets for therapeutic intervention.
Web | DOI | Zenodo | Preprint
Maccallini, Paolo
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of poorly understood etiology.
We performed a meta-analysis of two European-ancestry ME/CFS genome-wide association studies (GWAS) with no overlap in subjects, DecodeME and Million Veteran Program, comprising a total of 19,470 cases and 699,111 controls. Post-GWAS analyses investigated the association between ME/CFS and specific tissues, cell types, cellular components, and canonical pathways. Findings were independently evaluated for replication against a module of ME/CFS risk genes previously prioritized by machine learning applied to rare coding variants from whole-genome sequencing (WGS) of ME/CFS cases and controls of European ancestry.
Tissue enrichment analysis implicated multiple brain regions and the pituitary, with no peripheral tissue reaching significance, and three survived Bonferroni-corrected replication. Gene-set analysis identified multiple neuronal and synaptic gene sets, several of which were independently replicated, with glutamatergic synapses as the most specific replicated signal. Cell-type analysis identified independent replicated signals in distinct neuronal populations of subcortical and cerebellar regions.
These results suggest a role for synaptic function in specific brain regions in the pathogenesis of ME/CFS, with convergent support from both common and rare variant data. Larger studies are needed to confirm these findings and to identify specific targets for therapeutic intervention.
Web | DOI | Zenodo | Preprint
Jonathan Edwards
Senior Member (Voting Rights)
Were you aware of this one @James Cox ?
ME/CFS Science Blog
Senior Member (Voting Rights)
This is impressive work and well worth an in depth-read!
It follows the same line of reasoning we've been talking about on the forum fore more than a year, based on both the DecodeME data on common mutations and Mark Synder study on rare mutations hinting at neural synapses in the pathology of ME/CFS. But Paolo has done it in a more formal and persuasive way.
A first important addition is that he managed to add the 3891 ME/CFS cases from the Million Veteran Program (MVP) to the 15,579 from DecodeME in a meta-analysis. Paolo said he wanted to add cases from other genetic databases as well such as the UK biobank or FinnGenn, but that gave the issue that some of the controls overlapped. So this (DecodeME + MVP) is the biggest meta-analysis he could do.
Those from MVP were based on ICD-codes and with a prevalences of around 1.5% they might contain a lot of false positives (patients label ME/CFS who might not have it). But the bump in statistical power was just enough to get a lot of interesting results.
Paolo used the MAGMA tool that uses database on gene expression to see if the DNA results from ME/CFS patients are enriched in a particular group of genes or tissue. The DecodeME preprint did this as well and we (mostly forestglip) played around with this on the forum as well, showing it mostly pointed to the brain. But with the added MVP samples, Paolo seem to have gotten much stronger result implicating synapses in multiple ways.
The second interesting thing he added is that he used these gene sets from MAGMA and tested them in the Snyder study that used rare mutations. Several of these gene sets were replicated. Here are the important paragraphs that describe this approach:
The tissue results were similar to those from DecodeME alone I believe (various brain regions), but using various gene expression databases, Paolo found significant hits for particular brain cell types, most notably:
- the eccentric medium spiny neuron (eMSN) in the claustrum
- glutamatergic neuron in cerebellar white matter
It follows the same line of reasoning we've been talking about on the forum fore more than a year, based on both the DecodeME data on common mutations and Mark Synder study on rare mutations hinting at neural synapses in the pathology of ME/CFS. But Paolo has done it in a more formal and persuasive way.
A first important addition is that he managed to add the 3891 ME/CFS cases from the Million Veteran Program (MVP) to the 15,579 from DecodeME in a meta-analysis. Paolo said he wanted to add cases from other genetic databases as well such as the UK biobank or FinnGenn, but that gave the issue that some of the controls overlapped. So this (DecodeME + MVP) is the biggest meta-analysis he could do.
Those from MVP were based on ICD-codes and with a prevalences of around 1.5% they might contain a lot of false positives (patients label ME/CFS who might not have it). But the bump in statistical power was just enough to get a lot of interesting results.
Paolo used the MAGMA tool that uses database on gene expression to see if the DNA results from ME/CFS patients are enriched in a particular group of genes or tissue. The DecodeME preprint did this as well and we (mostly forestglip) played around with this on the forum as well, showing it mostly pointed to the brain. But with the added MVP samples, Paolo seem to have gotten much stronger result implicating synapses in multiple ways.
The second interesting thing he added is that he used these gene sets from MAGMA and tested them in the Snyder study that used rare mutations. Several of these gene sets were replicated. Here are the important paragraphs that describe this approach:
I think this is quite big, because it's not just about DecodeME (one study anymore) or even one approach (GWAS of common alleles).
The tissue results were similar to those from DecodeME alone I believe (various brain regions), but using various gene expression databases, Paolo found significant hits for particular brain cell types, most notably:
- the eccentric medium spiny neuron (eMSN) in the claustrum
- glutamatergic neuron in cerebellar white matter
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ME/CFS Science Blog
Senior Member (Voting Rights)
These were the 5 hits in the meta-analysis. The one on chromosome 17 for CA10 is not there but we do have a new one on chromosome 19.
Paolo provided the GRCh38 location in the supplementary material:
When I looked up the location on chr 19 on LocusZoom I got the following picture:
TSHZ3 seems to be involved in neural development.
Paolo provided the GRCh38 location in the supplementary material:
| topLeadSNP | GRCh38 | GRCh37 |
| rs2503773 | 6:98089269:A:G | 6:98537145:A:G |
| rs12579722 | 12:118125397:T:C | 12:118563202:T:C |
| rs7165327 | 15:54866724:A:G | 15:55158922:A:G |
| rs1982935 | 19:31366884:C:T | 19:31857790:C:T |
| rs4810894 | 20:48916462:A:G | 20:47532999:A:G |
When I looked up the location on chr 19 on LocusZoom I got the following picture:
TSHZ3 seems to be involved in neural development.
Jonathan Edwards
Senior Member (Voting Rights)
I wonder if people with ME/CFS want to be thought of as medium spiny and in the claustrum?
I must admit I had not thought of that!
ME/CFS Science Blog
Senior Member (Voting Rights)
There have been so many weird and denigrating names for our disease: chronic fatigue syndrome, post-exertional malaise, sickness behavior, photophobia.
If anything it must mean we're on the right track with "eccentric medium spiny neuron (eMSN) in the claustrum"!