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Genome-wide association study of severity in multiple sclerosis

Genes & Immunity volume 12, pages 615–625 (2011)Cite this article

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Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

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Acknowledgements

This work was supported by the National Institutes of Health (NS049477, NS032830, MH065215, NS067305, AI076544), the Wellcome Trust (084702/Z/08/Z) and the Cambridge NIHR Biomedical Research Centre. We appreciated the many helpful comments and suggestions from Paola Bronson and Patricia P Ramsay. All study participants were recruited in agreement with protocols of the institutional review board at each institution. For a full list of members of the IMSGC, see http://www.imsgc.org/.

Author contributors: Contributing authors to this work are Farren BS Briggs (UC Berkeley), Xiaorong Shao (UC Berkeley), Benjamin A Goldstein (UC Berkeley), Jorge R Oksenberg (UC San Francisco), Lisa F Barcellos (UC Berkeley) and Philip L de Jager (Brigham & Women's Hospital and Harvard Medical School). LFB and PLD contributed equally to this work. PLD is a Harry Weaver Neuroscience Scholar of the National MS Society. FBSB is a National MS Society Postdoctoral Fellow.

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Author notes

  1. Dr LF Barcellos, Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, 209 Hildebrand Hall, University of California, Berkeley, CA 94720, USA. E-mail: lbarcello@genepi.berkeley.edu

  2. Dr PL De Jager, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, and Program in Medical & Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02139, USA. E-mail: pdejager@rics.bwh.harvard.edu

Consortia

International Multiple Sclerosis Genetics Consortium

  • Farren B S Briggs
  • , Xiaorong Shao
  • , Benjamin A Goldstein
  • , Jorge R Oksenberg
  • , Lisa F Barcellos
  •  & Philip L De Jager

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The authors declare no conflict of interest.

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Contributors Farren BS Briggs Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, UC Berkeley. Xiaorong Shao Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, UC Berkeley; Division of Biostatistics, School of Public Health, UC Berkeley. Benjamin A Goldstein Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, UC Berkeley; Division of Biostatistics, School of Public Health, UC Berkeley. Jorge R Oksenberg Department of Neurology, School of Medicine, UC San Francisco; Institute for Human Genetics, School of Medicine, UC San Francisco. Lisa F Barcellos Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, UC Berkeley. Philip L De Jager Program in NeuroPsychiatric Genomics, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Boston; Program in Medical & Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA.

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International Multiple Sclerosis Genetics Consortium. Genome-wide association study of severity in multiple sclerosis. Genes Immun 12, 615–625 (2011). https://doi.org/10.1038/gene.2011.34

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