On the role of risk-associated genetic loci in modulating clinical course in multiple sclerosis

Multiple sclerosis (MS) is a chronic and immune-mediated central nervous system condition characterized by inflammation and demyelination. Large genome-wide association studies (GWAS) have identified 110 non-human leukocyte antigen (HLA) and several HLA MS risk variants. However, the relationship between MS risk-associated single nucleotide polymorphisms (SNPs) and MS clinical course has not been well studied. Despite good success in identifying a number of risk variants, several large GWAS studies have made comparatively little progress in finding associations with MS clinical course. Moreover, these risk SNPs only can explain 28% of MS risk. This brings one question: whether these risk SNPs influence MS clinical course? This thesis first presents an overview of MS, including its clinical symptom & diagnosis, the epidemiology of MS, and particularly the role of genetic factors in MS. Following from this is the report of my work evaluating the role of MS risk-associated single nucleotide polymorphisms (SNPs) in modulating clinical course in early MS. Utilising a longitudinal cohort study of persons who have had a first demyelinating event suggestive of, but not yet diagnostic of MS and then followed for five years, we found: Seven non-HLA SNPs predicted relapse and/or CDMS, and seven other non-HLA SNPs predicted the annualised change in disability status (ΔEDSS, as measured by Expanded Disability Status Scale). Following from this, we generated two genetic risk scores (GRS) based on those identified risk SNPs associated with CDMS/relapse and disability progression, which each significantly predicted each outcome in a significant, dose-dependent manner: Patients having >5 risk genotypes had a 6-fold greater risk of CDMS and relapse compared to those with <2; Those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared to those with <2, and the CGRS model explained 32% of the variance in disability. In summary, our findings of longitudinal data demonstrate that MS susceptibility genes predicted worse MS clinical course (that is, conversion to active disease, relapse risk and disability progression), suggesting that the genetic drivers of MS progression are polygenic. These findings may aid in targeting patients of high disease risk and potentially in early prevention and treatment, but replication is warranted.