Not all roads lead to the immune system: The genetic basis of multiple sclerosis severity

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10−7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes ..., Data collection:
Participants of European descent were recruited from eight tertiary-referral multiple sclerosis-specialist centres, from three countries (Australia, Spain, and Czech Republic), participating in the MSBase Registry. MSBase is an international, prospective, observational, multiple sclerosis clinical outcomes registry, registered with the World Health Organization International Clinical Trials Registry Platform, ID ACTRN12605000455662. Clinical data used to derive phenotypic information were entered by neurologists in, or near real-time including: participant demographics, disease phenotype, expanded disability status scale (EDSS) scores, relapse information, and disease-modifying therapy use. Clinical assessments occur on average every 6 months.
This study was approved by the Melbourne Health Human Research Ethics Committee, and by institutional review boards at all participating centres. All participants gave written informed consent for participation in the MSBase Regis..., Data files can be opened with Excel.