Publication
Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement
Publisher:
Cold Spring Harbor Laboratory
Date:
06-02-2022
DOI:
10.1101/2022.02.04.22270362
Abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS 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 MS Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 in iduals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.