Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Paolo Maccallini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9702020/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Bioinformatics Medical Genetics ME/CFS myalgic encephalomyelitis genome-wide association study meta-analysis METAL MAGMA synapse post-GWAS Full Text Additional Declarations The authors declare no competing interests. Supplementary Files S1File.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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