Abstract
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.
GLOSSARY
- 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
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.
Supplemental data at Neurology.org/ng
- Received December 4, 2015.
- Accepted in final form June 16, 2016.
- © 2016 American Academy of Neurology
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