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 in which immune, vascular, neuroinflammatory, and metabolic disturbances are frequently described, yet their causal roles remain unclear. Leveraging genome-wide summary statistics from the DecodeME study 15579 cases), we used genetic correlation, shared pleiotropic heritability, and Mendelian randomization to test whether these proposed biological domains have a genetic basis in ME/CFS. Across 22 auxiliary traits, representing five broad mechanistic domains, we observed significant positive genetic correlations for traits of cellular energetics, neurovascular regulation, and epithelial barrier–microbiome function. Migraine and irritable bowel syndrome, proxies for neurovascular dysregulation and barrier–microbiome disturbance, showed the strongest genetic overlap with ME/CFS, each contributing substantially to shared pleiotropy. In contrast, platelet/immunothrombotic and inflammatory traits showed smaller but still measurable genetic correlations and pleiotropic contributions. Energetics-related traits, including type 2 diabetes and lactate, displayed consistent genetic correlation but comparably low shared pleiotropy, suggesting that metabolic inflexibility may act through broader physiological networks. Mendelian randomization analyses identified three biomarkers with evidence for a causal contribution to ME/CFS: higher mitochondrial DNA copy number was protective, whereas increased glycoprotein acetyls (systemic inflammation) and mean platelet volume (platelet activation) increased disease risk. Together, these results show that ME/CFS susceptibility is shaped by interacting pathways involving barrier–microbiome dysfunction, neurovascular instability, chronic inflammation, platelet activation, and impaired cellular energetics. This genetically anchored framework highlights candidate mechanisms for biomarker and therapeutic development in ME/CFS and PAIS.