TY - JOUR

T1 - Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies

AU - George, Michaela F

AU - Briggs, Farren B S

AU - Shao, Xiaorong

AU - Gianfrancesco, Milena A

AU - Kockum, Ingrid

AU - Harbo, Hanne F

AU - Celius, Elisabeth G

AU - Bos, Steffan D

AU - Hedström, Anna Karin

AU - Shen, Ling

AU - Bernstein, Allan

AU - Alfredsson, Lars

AU - Hillert, Jan

AU - Olsson, Tomas

AU - Patsopoulos, Nikolaos A

AU - De Jager, Philip L

AU - Oturai, Annette B

AU - Søndergaard, Helle B

AU - Sellebjerg, Finn

AU - Sorensen, Per S

AU - Gomez, Refujia

AU - Caillier, Stacy J

AU - Cree, Bruce A C

AU - Oksenberg, Jorge R

AU - Hauser, Stephen L

AU - D'alfonso, Sandra

AU - Leone, Maurizio A

AU - Martinelli-Boneschi, Filippo

AU - Sorosina, Melissa

AU - van der Mei, Ingrid

AU - Taylor, Bruce V

AU - Zhou, Si-Yuan

AU - Schaefer, Catherine A

AU - Barcellos, Lisa F

PY - 2016/8

Y1 - 2016/8

N2 - 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.

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.

U2 - 10.1212/NXG.0000000000000087

DO - 10.1212/NXG.0000000000000087

M3 - Journal article

C2 - 27540591

VL - 2

JO - Neurology: Genetics

JF - Neurology: Genetics

SN - 2376-7839

IS - 4

M1 - e87

ER -