{
  "abstract": "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating female-biased disease with neither diagnostic biomarkers nor effective treatment nor well-understood aetiology. To investigate its biological basis, we used TarGene to perform a genome-wide association study in the UK Biobank with 1,268 ME/CFS cases, using electronic health records and survey responses to affirm ME/CFS status in cases, and non-ME/CFS status in controls. This analysis identified 176 variants as significantly associated with ME/CFS (false discovery rate < 5%). We then performed two replication studies, with similar phenotyping, in two disjoint, smaller cohorts in the UK Biobank and in the All of Us Research Program with 319 and 371 cases, respectively. Seven genomic ME/CFS risk loci replicated, although none were significant across all three cohorts. Fine-mapping at one replicated locus resolved a credible set colocalising with reduced CLYBL expression in putamen, in linkage disequilibrium with the replicated variant. However, the CLYBL Arg259 stop-gain variant was not associated with ME/CFS risk. Other replicated loci contained BICD1, GRIN2A, CSMD1 and RORA genes. No gene-by-sex or gene-by-deprivation interactions survived multiple-testing correction.\n\nSynopsis\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC=\"FIGDIR/small/26362115v1_ufig1.gif\" ALT=\"Figure 1\"> View larger version (20K): org.highwire.dtl.DTLVardef@12b51d4org.highwire.dtl.DTLVardef@1095197org.highwire.dtl.DTLVardef@cbd0a2org.highwire.dtl.DTLVardef@ee7482_HPS_FORMAT_FIGEXP M_FIG C_FIG No genomic risk loci for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have previously replicated across independent cohorts. We find seven variants associated with ME/CFS that replicate in disjoint biobank cohorts. O_LICases and controls are defined from multiple lines of evidence rather than a single diagnostic code. C_LIO_LINo variant replicates across all three cohorts, possibly reflecting differences in phenotype definition and population. C_LIO_LIResults provide candidate loci for follow-up into the biological mechanisms of ME/CFS. C_LI\n\nLay summaryMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common and disabling illness with a variety of symptoms. Additionally, little is known about the biological mechanisms that cause ME/CFS. The variety of symptoms and its unknown cause can make it difficult for healthcare professionals to diagnose people with ME/CFS reliably. This poses a significant challenge for ME/CFS research, as misdiagnoses may lead to errors in conclusions drawn from its study. Previously, studies have attempted to find biological mechanisms for ME/CFS by comparing the DNA of people with ME/CFS with the DNA of people without ME/CFS. These studies have identified regions of DNA linked to the illness; however, none of these links have been found in other ME/CFS studies. In our work, we compare the DNA of people with ME/CFS to the DNA of people without ME/CFS, where ME/CFS status is supported by multiple lines of evidence to reduce the likelihood of misdiagnoses in the participants selected for the study. We then use similar selection strategies, using multiple lines of evidence to repeat the study in independent groups of people. By doing so, we found seven regions of DNA linked to ME/CFS status in more than one study. Some of these links are close to or located in regions of DNA called genes. Genes produce molecules known as proteins, which are responsible for many functions in the human body. It is not currently possible to determine exactly whether genes near disease-linked regions of DNA cause disease, so we report nearby genes with the highest likelihood of linkage to ME/CFS. We also investigated whether the linkage of these regions changed when we further compared groups based on sex or socioeconomic status, but no conclusive results were found. Comparison with the larger DecodeME study showed no overlapping results.",
  "abstract_shown": true,
  "affiliations": [
    "University of Edinburgh"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "J. Slaughter"
    },
    {
      "name": "O. Labayle"
    },
    {
      "name": "B. Roskams-Hieter"
    },
    {
      "name": "J. J. Dibble"
    },
    {
      "name": "S. J. McGrath"
    },
    {
      "name": "S. V. Beentjes"
    },
    {
      "name": "A. Khamseh"
    },
    {
      "name": "C. P. Ponting"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/25h3ee1vwqjr4.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.09.26362115",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362115v1.full",
  "id": "25h3ee1vwqjr4",
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  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362115v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "2738|Fibromyalgia and Chronic Fatigue Syndrome Research"
    ]
  ],
  "openalex": "W7212621394",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362115v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/25h3ee1vwqjr4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:31Z",
      "native_id": "10.64898/2026.09.09.26362115",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362115v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Seven replicated genomic associations of myalgic encephalomyelitis/chronic fatigue syndrome: a biobank study",
  "title_text": "Seven replicated genomic associations of myalgic encephalomyelitis/chronic fatigue syndrome: a biobank study",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:31Z",
  "url": "https://research.draconitic.com/paper/25h3ee1vwqjr4",
  "venue": "medRxiv",
  "versions": []
}