Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome.

AIM To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores. METHODS DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes. RESULTS We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes. CONCLUSION ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.

[1]  James F. Jones,et al.  An evaluation of exclusionary medical/psychiatric conditions in the definition of chronic fatigue syndrome , 2009, BMC medicine.

[2]  A. Baccarelli,et al.  Storage conditions and stability of global DNA methylation in placental tissue. , 2013, Epigenomics.

[3]  Patrick O. McGowan,et al.  The epigenetic landscape of myalgic encephalomyelitis/chronic fatigue syndrome: deciphering complex phenotypes. , 2017, Epigenomics.

[4]  M. Esteller,et al.  Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome , 2011, Epigenetics.

[5]  Paul Kellam,et al.  Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. , 2008, The Journal of infectious diseases.

[6]  A. Light,et al.  Differences in Metabolite-Detecting, Adrenergic, and Immune Gene Expression After Moderate Exercise in Patients With Chronic Fatigue Syndrome, Patients With Multiple Sclerosis, and Healthy Controls , 2012, Psychosomatic medicine.

[7]  N. Unterwalder,et al.  Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome , 2014, PloS one.

[8]  J. DeLuca,et al.  Personality dimensions in the chronic fatigue syndrome: a comparison with multiple sclerosis and depression. , 1996, Journal of psychiatric research.

[9]  A. Oshlack,et al.  SWAN: Subset-quantile Within Array Normalization for Illumina Infinium HumanMethylation450 BeadChips , 2012, Genome Biology.

[10]  E. Bullmore,et al.  Hubs of brain functional networks are radically reorganized in comatose patients , 2012, Proceedings of the National Academy of Sciences.

[11]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[12]  Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue , 2009, Population health metrics.

[13]  R. Weksberg,et al.  Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray , 2013, Epigenetics.

[14]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Buchwald,et al.  Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. , 1994, Archives of internal medicine.

[16]  A. Rademaker,et al.  A community-based study of chronic fatigue syndrome. , 1999, Archives of internal medicine.

[17]  The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs) , 2014, Molecular Neurobiology.

[18]  M. Szyf,et al.  The effects of pH on DNA methylation state: In vitro and post-mortem brain studies , 2008, Journal of Neuroscience Methods.

[19]  M. Lenzenweger.  ENDOPHENOTYPE, INTERMEDIATE PHENOTYPE, BIOMARKER: DEFINITIONS, CONCEPT COMPARISONS, CLARIFICATIONS , 2013, Depression and anxiety.

[20]  D. Staines,et al.  A comparison of health status in patients meeting alternative definitions for chronic fatigue syndrome/myalgic encephalomyelitis , 2014, Health and Quality of Life Outcomes.

[21]  David C Hoaglin,et al.  Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. , 2003, Archives of internal medicine.

[22]  S. Beck,et al.  Analysis pipelines and packages for Infinium HumanMethylation450 BeadChip (450k) data , 2015, Methods.

[23]  The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue. , 2006, Pharmacogenomics.

[24]  Paolo Vineis,et al.  Performance in Omics Analyses of Blood Samples in Long-Term Storage: Opportunities for the Exploitation of Existing Biobanks in Environmental Health Research , 2013, Environmental health perspectives.

[25]  Benjamin J. Raphael,et al.  Network propagation: a universal amplifier of genetic associations , 2017, Nature Reviews Genetics.

[26]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[27]  M. Maes.  Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms , 2009, Current opinion in psychiatry.

[28]  James R. Brown,et al.  No association found between the detection of either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus and chronic fatigue syndrome in a blinded, multi-site, prospective study by the establishment and use of the SolveCFS BioBank , 2014, BMC Research Notes.

[29]  Jiuyong Li,et al.  Identifying Cancer Subtypes from miRNA-TF-mRNA Regulatory Networks and Expression Data , 2016, PloS one.

[30]  Patrick O. McGowan,et al.  Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) , 2017, BMC Medical Genomics.

[31]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[32]  B. Ford,et al.  Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls , 2013, Clinical and experimental immunology.

[33]  Gordon Broderick,et al.  Gene Expression Correlates of Unexplained Fatigue , 2006, Pharmacogenomics.

[34]  D. Bell,et al.  Understanding long-term outcomes of chronic fatigue syndrome. , 2012, Journal of clinical psychology.

[35]  L. Morales,et al.  The RAND-36 measure of health-related quality of life , 2001, Annals of medicine.

[36]  Beate Peter,et al.  Motor sequencing deficit as an endophenotype of speech sound disorder: a genome-wide linkage analysis in a multigenerational family , 2012, Psychiatric genetics.

[37]  A. House,et al.  Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case–control study , 2003, Psychological Medicine.

[38]  Ø. Fluge,et al.  Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study , 2011, PloS one.

[39]  Zhuowen Tu,et al.  Similarity network fusion for aggregating data types on a genomic scale , 2014, Nature Methods.

[40]  M. Meeus,et al.  Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome , 2006, Clinical Rheumatology.

[41]  Suzanne D Vernon,et al.  Cost Effectiveness and Resource Allocation Open Access the Economic Impact of Chronic Fatigue Syndrome , 2022 .

[42]  J. Tost,et al.  DNA methylation: an introduction to the biology and the disease-associated changes of a promising biomarker. , 2009, Methods in molecular biology.

[43]  I. Mena,et al.  Myalgic encephalomyelitis: International Consensus Criteria , 2011, Journal of internal medicine.

[44]  Jin-Mann S. Lin,et al.  The economic impact of chronic fatigue syndrome in Georgia: direct and indirect costs , 2011 .

[45]  Nicholas G Martin,et al.  Contribution of genetic variation to transgenerational inheritance of DNA methylation , 2014, Genome Biology.

[46]  Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) , 2014, Journal of Clinical Pathology.

[47]  Marianna Aprile,et al.  RNA-Seq and human complex diseases: recent accomplishments and future perspectives , 2012, European Journal of Human Genetics.

[48]  James F. Jones,et al.  Psychiatric Comorbidity in Persons With Chronic Fatigue Syndrome Identified From the Georgia Population , 2009, Psychosomatic medicine.

[49]  Kefeng Li,et al.  Metabolic features of chronic fatigue syndrome , 2016, Proceedings of the National Academy of Sciences.

[50]  M. Leandro,et al.  Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross‐sectional study , 2016, Clinical and experimental immunology.

[51]  Dan Wang,et al.  IMA: an R package for high-throughput analysis of Illumina's 450K Infinium methylation data , 2012, Bioinform..

[52]  Eldon Emberly,et al.  Factors underlying variable DNA methylation in a human community cohort , 2012, Proceedings of the National Academy of Sciences.

[53]  U. Vollmer-Conna,et al.  An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. , 2006, Pharmacogenomics.

[54]  Tom R. Gaunt,et al.  Systematic identification of genetic influences on methylation across the human life course , 2016, Genome Biology.

[55]  A. Jablensky,et al.  Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition , 2011, Molecular Psychiatry.

[56]  Huiguang He,et al.  Combining Disrupted and Discriminative Topological Properties of Functional Connectivity Networks as Neuroimaging Biomarkers for Accurate Diagnosis of Early Tourette Syndrome Children , 2018, Molecular Neurobiology.

[57]  D. Papanicolaou,et al.  Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. , 2000, The Journal of clinical endocrinology and metabolism.

[58]  A. M. Ramsay,et al.  Myalgic encephalomyelitis--a persistent enteroviral infection? , 1990, Postgraduate medical journal.

[59]  C. Gieger,et al.  DNA methylation and body-mass index: a genome-wide analysis , 2014, The Lancet.

[60]  C. Dancey,et al.  Symptoms, impairment and illness intrusiveness–their relationship with depression in women with CFS/ME , 2008, Psychology & health.

[61]  Luba Kalaydjieva,et al.  Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. , 2005, American journal of human genetics.

[62]  J. Casanova,et al.  IL‐12Rβ1 Deficiency: Mutation Update and Description of the IL12RB1 Variation Database , 2013, Human mutation.

[63]  Junfeng Xia,et al.  Identification of ovarian cancer subtype-specific network modules and candidate drivers through an integrative genomics approach , 2015, Oncotarget.

[64]  Patrick O. McGowan,et al.  DNA Methylation Modifications Associated with Chronic Fatigue Syndrome , 2014, PloS one.

[65]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[66]  B. Bradley,et al.  DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain , 2015, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[67]  Ichigaku Takigawa,et al.  Annotating gene function by combining expression data with a modular gene network , 2007, ISMB/ECCB.

[68]  Evan E. Eichler,et al.  A Genotype-First Approach to Defining the Subtypes of a Complex Disease , 2014, Cell.

[69]  A. Rademaker,et al.  CFS prevalence and risk factors over time , 2011, Journal of health psychology.

[70]  Ian Hickie,et al.  The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study , 1994, Annals of Internal Medicine.

[71]  S. Kiani-Alikhan,et al.  Chronic fatigue syndrome, the immune system and viral infection , 2012, Brain, Behavior, and Immunity.

[72]  D. Nutt,et al.  Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis , 2009, Journal of Clinical Pathology.