PT  - JOURNAL ARTICLE
AU  - Michaela F. George
AU  - Farren B.S. Briggs
AU  - Xiaorong Shao
AU  - Milena A. Gianfrancesco
AU  - Ingrid Kockum
AU  - Hanne F. Harbo
AU  - Elisabeth G. Celius
AU  - Steffan D. Bos
AU  - Anna Hedström
AU  - Ling Shen
AU  - Allan Bernstein
AU  - Lars Alfredsson
AU  - Jan Hillert
AU  - Tomas Olsson
AU  - Nikolaos A. Patsopoulos
AU  - Philip L. De Jager
AU  - Annette B. Oturai
AU  - Helle B. Søndergaard
AU  - Finn Sellebjerg
AU  - Per S. Sorensen
AU  - Refujia Gomez
AU  - Stacy J. Caillier
AU  - Bruce A.C. Cree
AU  - Jorge R. Oksenberg
AU  - Stephen L. Hauser
AU  - Sandra D'Alfonso
AU  - Maurizio A. Leone
AU  - Filippo Martinelli Boneschi
AU  - Melissa Sorosina
AU  - Ingrid van der Mei
AU  - Bruce V. Taylor
AU  - Yuan Zhou
AU  - Catherine Schaefer
AU  - Lisa F. Barcellos
TI  - Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies
AID  - 10.1212/NXG.0000000000000087
DP  - 2016 Aug 01
TA  - Neurology Genetics
PG  - e87
VI  - 2
IP  - 4
4099  - http://ng.neurology.org/content/2/4/e87.short
4100  - http://ng.neurology.org/content/2/4/e87.full
SO  - Neurol Genet2016 Aug 01; 2
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