Preprint Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization, 2026, Wielscher et al

[forestglip]

Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization

Spoiler: Authors

Wielscher, Matthias; Vincenzi, Leonardo; Weninger, Wolfgang P; Schernhammer, Eva S

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute infection syndromes (PAIS) are multisystem disorders involving immune, vascular, neuroinflammatory, and metabolic abnormalities, yet the causal relevance of these processes remains unclear.

Using genome-wide summary statistics from DecodeME (15,579 cases), we performed genetic correlation, pleiotropic heritability, and Mendelian randomization analyses.

Across 22 auxiliary traits spanning five mechanistic domains, cellular energetics, neurovascular regulation, and barrier–microbiome function showed the strongest genetic overlap with ME/CFS, with migraine and irritable bowel syndrome contributing most to shared pleiotropy. Immunothrombotic related and inflammatory traits showed smaller but measurable genetic correlations. Energetics-related traits, including type 2 diabetes and blood lactate, displayed consistent genetic correlation but relatively low shared pleiotropy, suggesting that metabolic dysfunction may act through broader physiological networks.

Mendelian randomization identified three biomarkers with evidence for causal effects on ME/CFS risk: higher mitochondrial DNA copy number was protective, whereas increased glycoprotein acetyls and mean platelet volume increased risk.

Together, these findings indicate that ME/CFS susceptibility reflects interacting pathways involving barrier–microbiome dysfunction, neurovascular instability, inflammation, platelet activation, and impaired cellular energetics

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[Hoopoe]

This reminds that the other day I heard of a patient that had episodes where, in order to recover, he was forced to lie in a darkened quiet room for half or a whole day. The illness was migraines. I don't know what these episoders where triggered by; it sounded as if it they didn't occur often enough to interfere much with daily life, but were crippling when they occurred.

 

[forestglip]

Migraine, a common comorbidity of POTS reflecting impaired neurovascular reactivity (10), showed a clear positive genetic correlation with ME/CFS (rg = 0.45, p < 10⁻⁶). PHBC analyses mirrored this result: migraine exhibited substantial single-trait shared pleiotropy with ME/CFS, and its removal from the multi-trait model produced a marked reduction in shared pleiotropy, indicating that neurovascular dysregulation represents a key pleiotropic axis underlying ME/CFS risk.

I recently was interested in migraine because I found a large correlation using Google Trends scores, showing that [edit: US] states that search more for "chronic fatigue syndrome" tend to also search more for "migraine" and "migraine aura".

I previously also did genetic correlations using DecodeME summary stats against all the conditions in the UK BioBank and FinnGen using the Bigagwas platform. I just went back to check what the correlations were for ME/CFS with traits that relate to migraine:

Source	Trait code	Trait name	Genetic correlation (rg)	P value
UK BioBank	G43.gwas.imputed_v3.both_sexes	Diagnoses - main ICD10: G43 Migraine	0.4207	0.0063
UK BioBank	20002_1265.gwas.imputed_v3.both_sexes	Non-cancer illness code, self-reported: migraine	0.2132	6.34E-05
FinnGen	G6_MIGRAINE	Migraine-VI Diseases of the nervous system (G6_)	0.4425	1.62E-23
FinnGen	MIGRAINE_TRIPTAN	Migraine, single triptan purchase ok & required. ICD-code if available is included-Neurological endpoints	0.3206	7.48E-17

The correlation values with these traits seem fairly consistent with this study's correlation with migraine (rg = 0.45, p < 10⁻⁶).

The supplemental file says that the study used for migraine was Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program, which was done on a USA cohort. So the positive genetic correlation of ME/CFS with migraine seems consistent when comparing to migraine cases from three different countries: USA, UK, and Finland.

Considering that there is an increased risk for females for both migraine and ME/CFS, and that both conditions display light/sound sensitivity, this might be a good lead.

I haven't read a lot about it yet, but it seems that research on migraine is a bit further along in identifying mechanisms, such as the involvement of the trigeminal nerve and CGRP proteins.