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

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 Main Text