title: Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study.
abstract: 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.
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Gongbu
authors: G
authors: Pan
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Steve
authors: http://orcid.org/0000-0001-6521-3056
authors: S
authors: Simpson
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Ingrid
authors: I
authors: van der Mei
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Jac C
authors: JC
authors: Charlesworth
authors: National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Robyn
authors: R
authors: Lucas
authors: Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors: Anne-Louise
authors: AL
authors: Ponsonby
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Yuan
authors: Y
authors: Zhou
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Feitong
authors: F
authors: Wu
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors: Bruce V
authors: BV
authors: Taylor
mesh_terms: D000328:Adult; D001315:Australia; D016022:Case-Control Studies; D015331:Cohort Studies; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis* / Q000235:genetics*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D006680:HLA Antigens