BACKGROUNDMany genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear.OBJECTIVETo investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts.METHODSNorwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708).RESULTSThe total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P < 10(-22)). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts.CONCLUSIONThe MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.