RT Journal Article SR Electronic T1 Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e87 DO 10.1212/NXG.0000000000000087 VO 2 IS 4 A1 Michaela F. George A1 Farren B.S. Briggs A1 Xiaorong Shao A1 Milena A. Gianfrancesco A1 Ingrid Kockum A1 Hanne F. Harbo A1 Elisabeth G. Celius A1 Steffan D. Bos A1 Anna Hedström A1 Ling Shen A1 Allan Bernstein A1 Lars Alfredsson A1 Jan Hillert A1 Tomas Olsson A1 Nikolaos A. Patsopoulos A1 Philip L. De Jager A1 Annette B. Oturai A1 Helle B. Søndergaard A1 Finn Sellebjerg A1 Per S. Sorensen A1 Refujia Gomez A1 Stacy J. Caillier A1 Bruce A.C. Cree A1 Jorge R. Oksenberg A1 Stephen L. Hauser A1 Sandra D'Alfonso A1 Maurizio A. Leone A1 Filippo Martinelli Boneschi A1 Melissa Sorosina A1 Ingrid van der Mei A1 Bruce V. Taylor A1 Yuan Zhou A1 Catherine Schaefer A1 Lisa F. Barcellos YR 2016 UL http://ng.neurology.org/content/2/4/e87.abstract AB Objective: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS).Methods: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ≤5 vs >5 and MSSS of <2.5 vs ≥7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01.Results: A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ≥10 years, associations were null (p value ≥0.05). No SNP was associated with disease severity after adjusting for multiple testing.Conclusions: The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.CI=confidence interval; EAE=experimental autoimmune encephalomyelitis; EDSS=Expanded Disability Severity Scale; GRS=unweighted genetic risk score; GWAS=genome-wide association studies; KPNC=Kaiser Permanente Medical Care Plan in the Northern California Region; MHC=major histocompatibility complex; MS=multiple sclerosis; MSSS=Multiple Sclerosis Severity Score; OR=odds ratio; SNP=single nucleotide polymorphism; UCSF=University of California at San Francisco; wGRS=weighted genetic risk score