{
  "abstract": "Background Predicting response to treatment and long-term disability in multiple sclerosis (MS) remains challenging. In other complex diseases, combining genetic risk variants has enabled the detection of relevant clinical endophenotypes associated with important outcomes, but this strategy has never been applied to MS.Methods We applied unsupervised hierarchical clustering to genomic risk scores in a prospective Welsh MS cohort (n=1455) and replicated the findings in the postmortem Netherlands Brain Bank (NBB) MS (NBB-MS) cohort (n=272). Disease progression was assessed using survival analysis to determine the time to Expanded Disability Status Scale (EDSS) milestones.Results Three genomic clusters were identified, each with similar genetic profiles. Baseline demographics did not differ between clusters. Welsh patients in cluster 1 attained EDSS 6 and EDSS 8 significantly later than clusters 2 and 3 (by 6 years, p=3×10 −3 and 13 years, p=0.02, respectively). These findings were replicated in the NBB-MS cohort (6-year delay to EDSS 6 for cluster 1 vs 2, p=0.04). Genomic clustering independently predicted disease progression (HRs 1.3–2.0, all p<0.05), beyond established risk factors. Clusters 2 and 3 showed a greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients receiving disease-modifying treatments had delayed progression to EDSS 6 (p=3×10−³), while no such benefit was observed in clusters 1 or 3. Cluster 2 patients also had earlier onset of symptoms, including dysphagia (p=0.02) and spasticity (p=8×10−⁴) in the NBB-MS cohort.Conclusions Genetic clustering reveals clinically meaningful MS subtypes with distinct prognoses and treatment responses, highlighting its potential role in precision medicine for MS management.",
  "authors": [
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK",
        "Mental Health and Clinical Neuroscience Unit, University of Nottingham, Nottingham, England, UK"
      ],
      "name": "Karim L Kreft"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Centre Groningen, Groningen, The Netherlands",
        "Machine Learning Lab, Data Science, University of Groningen, Groningen, Netherlands"
      ],
      "name": "Nienke J Mekkes"
    },
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK"
      ],
      "name": "Emeka Uzochukwu"
    },
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK"
      ],
      "name": "Sam Loveless"
    },
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK"
      ],
      "name": "Ray Wynford-Thomas"
    },
    {
      "affiliations": [
        "Department of Neurology, Royal Gwent Hospital, Newport, England, UK"
      ],
      "name": "Katharine Elizabeth Harding"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital of Wales, Cardiff, Wales, UK"
      ],
      "name": "Mark Wardle"
    },
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK"
      ],
      "name": "Peter Holmans"
    },
    {
      "affiliations": [
        "Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK"
      ],
      "name": "J William L Brown"
    },
    {
      "affiliations": [
        "Population Health Sciences, University of Bristol Medical School, Bristol, UK"
      ],
      "name": "Michael Lawton"
    },
    {
      "affiliations": [
        "Helen Durham Centre for Neuroinflammatory Disease, University Hospital of Wales, Cardiff, Cardiff, UK"
      ],
      "name": "Emma Clare Tallantyre"
    },
    {
      "affiliations": [
        "Department of Biomedical Sciences, Section Molecular Neurobiology, University Medical Centre Groningen, Groningen, The Netherlands",
        "Machine Learning Lab, Data Science, University of Groningen, Groningen, Netherlands"
      ],
      "name": "Inge R Holtman"
    },
    {
      "affiliations": [
        "Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, Wales, UK",
        "Department of Neurology, University Hospital of Wales, Cardiff, Wales, UK"
      ],
      "name": "Neil P Robertson"
    }
  ],
  "title": "Genetic subtypes associated with multiple sclerosis severity and response to treatment",
  "uid": "ed8341aa-5f50-5f04-acb8-f0ee9fc720e0"
}