Multiple sclerosis (MS) is a chronic neurological disease, causing progressive disability, with approximately half of its genetic basis remains unexplained. This project will identify rare genetic variants associated with MS risk and progression using UK Biobank’s comprehensive genetic and health data. We will analyze whole exome sequencing data from MS patients and control participants. Our study has three complementary aims: Aim 1: Rare Variant Discovery – We will perform association tests to identify rare coding variants and genes that increase MS risk or influence disease severity. Aim 2: Genetic Risk Score Stratification – We will use polygenic risk scores using known MS-associated common variants to identify patients with low common variant burden. We hypothesize that these individuals likely harbor rare variants with larger effects, enabling more efficient discovery of high-impact genetic factors. Aim 3: Clinical Phenotype Associations – Brain imaging and biomarker data will be examined for associations between rare variants and MS-related outcomes including brain atrophy, white matter lesion burden, disability proxies, comorbidities, and inflammatory biomarkers, as available. This research aims to reveal novel therapeutic targets by identifying genes and biological pathways critical to MS development and progression.
