Genotype–phenotype correlation for non-HLA disease associated risk alleles in multiple sclerosis

BackgroundRecent advances in MS genetics have led to the successful identification of a number of novel disease associated non-HLA genes. It is now becoming possible to begin to analyse the possible effects of these genes on aspects of disease phenotype where longitudinal clinical data is available.ObjectiveWe examined phenotypic impact of 10 non-HLA disease associated single nucleotide polymorphisms (SNPs) in 1003 patients with MS followed for an average of 14.1 years.MethodsAssociation of SNPs with time to established disability milestones (Expanded Disability Status Scale (EDSS) 4.0, 6.0, 8.0), onset of secondary progression and cross-sectional aspects of early phenotype were tested using survival analysis.ResultsNo SNP was associated with systematic deflection in time to disability milestones, age at onset or time to secondary progression.ConclusionsGenotypic information from non-HLA associated SNPs is unlikely to inform individual patient prognosis in the clinical setting although minor phenotypic effects operative at specific phases of disease cannot be excluded. This preliminary study provides a framework for future genotype–phenotype analysis in MS and will need to be replicated in independent patient cohorts.

► We examined impact of genotype variation on disease phenotype in multiple sclerosis. ► No genotype was associated with time to fixed disability at all stages of disease. ► rs34536443 was associated with prolonged time to EDSS 4. ► rs12122721 was associated with shorter time to EDSS 8 and cerebellar disease onset.