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August 2016; 2 (4) ArticleOpen Access

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

Michaela F. George, Farren B.S. Briggs, Xiaorong Shao, Milena A. Gianfrancesco, Ingrid Kockum, Hanne F. Harbo, Elisabeth G. Celius, Steffan D. Bos, Anna Hedström, Ling Shen, Allan Bernstein, Lars Alfredsson, Jan Hillert, Tomas Olsson, Nikolaos A. Patsopoulos, Philip L. De Jager, Annette B. Oturai, Helle B. Søndergaard, Finn Sellebjerg, Per S. Sorensen, Refujia Gomez, Stacy J. Caillier, Bruce A.C. Cree, Jorge R. Oksenberg, Stephen L. Hauser, Sandra D'Alfonso, Maurizio A. Leone, Filippo Martinelli Boneschi, Melissa Sorosina, Ingrid van der Mei, Bruce V. Taylor, Yuan Zhou, Catherine Schaefer, Lisa F. Barcellos
First published August 4, 2016, DOI: https://doi.org/10.1212/NXG.0000000000000087
Michaela F. George
Author affiliations are listed at the end of the article.
PhD
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Farren B.S. Briggs
PhD
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Xiaorong Shao
MA
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Milena A. Gianfrancesco
MPH
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Ingrid Kockum
PhD
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Hanne F. Harbo
MD, PhD
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Elisabeth G. Celius
MD, PhD
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Steffan D. Bos
MSc, PhD
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Anna Hedström
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Ling Shen
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Allan Bernstein
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Lars Alfredsson
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Jan Hillert
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Tomas Olsson
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Nikolaos A. Patsopoulos
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Philip L. De Jager
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Annette B. Oturai
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Helle B. Søndergaard
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Finn Sellebjerg
MD, PhD, DMSc
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Per S. Sorensen
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Refujia Gomez
BS
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Stacy J. Caillier
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Bruce A.C. Cree
MD, PhD, MAS
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Jorge R. Oksenberg
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Stephen L. Hauser
MD
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Sandra D'Alfonso
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Maurizio A. Leone
MD
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Filippo Martinelli Boneschi
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Melissa Sorosina
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Ingrid van der Mei
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Bruce V. Taylor
MD
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Yuan Zhou
MS
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Catherine Schaefer
PhD
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Lisa F. Barcellos
PhD, MPH
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Full PDF
Citation
Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies
Michaela F. George, Farren B.S. Briggs, Xiaorong Shao, Milena A. Gianfrancesco, Ingrid Kockum, Hanne F. Harbo, Elisabeth G. Celius, Steffan D. Bos, Anna Hedström, Ling Shen, Allan Bernstein, Lars Alfredsson, Jan Hillert, Tomas Olsson, Nikolaos A. Patsopoulos, Philip L. De Jager, Annette B. Oturai, Helle B. Søndergaard, Finn Sellebjerg, Per S. Sorensen, Refujia Gomez, Stacy J. Caillier, Bruce A.C. Cree, Jorge R. Oksenberg, Stephen L. Hauser, Sandra D'Alfonso, Maurizio A. Leone, Filippo Martinelli Boneschi, Melissa Sorosina, Ingrid van der Mei, Bruce V. Taylor, Yuan Zhou, Catherine Schaefer, Lisa F. Barcellos
Neurol Genet Aug 2016, 2 (4) e87; DOI: 10.1212/NXG.0000000000000087

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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.

  • See editorial

  • Supplemental data at Neurology.org/ng

  • Received December 4, 2015.
  • Accepted in final form June 16, 2016.
  • © 2016 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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