Genetics

This blog post reviews the 2023 Brain article by Jokubaitis and colleagues examining the genetic architecture of multiple sclerosis (MS) severity using longitudinal disability data from the MSBase registry. It explains why severity is genetically and biologically distinct from disease susceptibility, summarizes the study’s genome-wide analyses showing no major-effect variants but measurable polygenic contributions, and highlights how machine-learning models that aggregate thousands of common variants substantially improve discrimination of mild versus severe trajectories compared with baseline clinical variables alone. The post also discusses sex-stratified findings and time-to-disability milestone validation, and interprets tissue and pathway enrichment results that point toward central nervous system–centric mechanisms (including synaptic, mitochondrial, and remyelination-related biology). Finally, it outlines translational implications and key limitations, emphasizing the need for independent replication and functional follow-up before genetic severity prediction can be incorporated into routine MS prognostication.