Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep. The disease mechanism of ME/CFS is unknown, with no effective curative treatments. In this study, we present a multi-site ME/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME/CFS based on personal rare variants, but also links genetic risk to various ME/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations. Transcriptome and network analyses highlight the functional importance of these genes across a wide range of tissues and cell types, including the central nervous system (CNS) and immune cells. Patient-derived multi-omics data implicate reduced expression of ME/CFS risk genes within ME/CFS patients, including in the plasma proteome, and the transcriptomes of B and T cells, especially cytotoxic CD4 T cells, supporting their disease relevance. Pan-phenotype analysis of ME/CFS genes further reveals the genetic correlation between ME/CFS and other complex diseases and traits, including depression and long COVID-19. Overall, HEAL2 provides a candidate genetic-based diagnostic tool for ME/CFS, and our findings contribute to a comprehensive understanding of the genetic, molecular, and cellular basis of ME/CFS, yielding novel insights into therapeutic targets. Our deep learning model also offers a potent, broadly applicable framework for parallel rare variant analysis and genetic prediction for other complex diseases and traits.
### Competing Interest Statement
M.P.S is a cofounder and scientific advisor of Crosshair Therapeutics, Exposomics, Filtricine, Fodsel, iollo, InVu Health, January AI, Marble Therapeutics, Mirvie, Next Thought AI, Orange Street Ventures, Personalis, Protos Biologics, Qbio, RTHM, SensOmics. M.P.S. is a scientific advisor of Abbratech, Applied Cognition, Enovone, Jupiter Therapeutics, M3 Helium, Mitrix, Neuvivo, Onza, Sigil Biosciences, TranscribeGlass, WndrHLTH, Yuvan Research. M.P.S. is a cofounder of NiMo Therapeutics. M.P.S. is an investor and scientific advisor of R42 and Swaza. M.P.S. is an investor in Repair Biotechnologies. M.R.H. is a member of the scientific advisory boards of the Open Medicine Foundation, Solve CFS/ME, the WE&ME Foundation, and Simmaron Research.
### Funding Statement
This study is supported by the Candace & Bert Forbes gift funds (to M.P.S.). M.J.Z. acknowledges the support of the Shurl and Kay Curci Foundation. NIH U54NS105541, an initial grant provided to the Cornell ME/CFS Collaborative Research Center, was co-funded by the National Institute of Neurological Disorders and Stroke, National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, and the Office of the Director. A renewal grant was made to the Cornell Center from NIH NIAID: U54AI178855.
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Stanford cohort was approved by Stanford IRB team (IRB-40146). Cornell cohort was approved by Institutional Review Boards at Cornell University (IRB# 0001855), Ithaca College (IRB# 1017-12D), or Weill Cornell Medicine (IRB# 1708018518). UK CureME study was approved by University College London Biobank Ethical Review Committee (NC2021.24).
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
All data produced in the present study are available upon reasonable request to the authors
