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Research paper
Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study
  1. Gongbu Pan1,
  2. Steve Simpson Jr1,
  3. Ingrid van der Mei1,
  4. Jac C Charlesworth1,
  5. Robyn Lucas2,
  6. Anne-Louise Ponsonby3,
  7. Yuan Zhou1,
  8. Feitong Wu1,
  9. AusLong/Ausimmune Investigator Group,
  10. Bruce V Taylor1
  1. 1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  2. 2National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australian Capital Territory, Australia
  3. 3Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia
  1. Correspondence to Professor Bruce V Taylor, Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Hobart, TAS 7000, Australia; Bruce.Taylor{at}


Background The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies.

Methods Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS).

Results We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort.

Conclusions These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic.

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  • A full list of members of the AusLong/Ausimmune Investigator Group is provided in the Acknowledgments.

  • Contributors GP did the statistical analysis under supervision by SS, BVT and IvdM. GP and SS did the interpretation, and wrote the manuscript, with input from YZ, FW, IvdM, JCC, RL, A-LP and BVT. IvdM, RL, A-LP and BVT conceived and designed the study. All authors revised and approved the final version of the manuscript. BVT had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding The AusLong cohort study was supported by the National Health and Medical Research Council of Australia (Grant reference number: 54922).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Nine regional Human Research Ethics Committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.