Toward a Disease Module for ME/CFS: A Network-Based Gene Prioritization

BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition with unclear etiology and no FDA-approved treatment. Recent studies suggest a possible genetic contribution to its pathogenesis. ObjectiveThis study aims to identify candidate genes for ME/CFS using both empirical evidence from genome-wide and next-generation sequencing studies on monogenic cases and computational expansion based on protein-protein interaction networks. MethodsTwenty-two genes associated with ME/CFS were identified from relevant literature, including both common and rare variants. These genes were used as seeds in the STRING database to retrieve high-confidence interacting genes. A Random Walk with Restart (RWR) algorithm ranked 1063 candidate genes by their similarity to the seeds. The top 250 ranking genes were selected to define a disease module termed the ME/CFS module. This module was analysed for enrichment in metabolic pathways and disease associations. ResultsEnrichment analysis identified significant overlaps with sphingolipid metabolism and signaling, and energy-related pathways. Heme degradation, TP53-regulated metabolic genes, and thermogenesis were also identified as possibly contributing to the pathogenesis of ME/CFS. Overlaps with metabolic and neurodegenerative diseases were observed. ConclusionThe ME/CFS module captures biologically plausible mechanisms underlying ME/CFS, with a particular focus on lipid and energy metabolism. It also provides a tool for filtering exome and genome data for the study of Mendelian cases of ME/CFS.