International Multiple Sclerosis Genomics Consortium (IMSGC) Genome Wide Association Study of Multiple Sclerosis

The goal of this study is to perform a comprehensive allelic and genotypic association analysis of the entire human genome in multiple sclerosis. The recent definitive linkage genome screen demonstrated that there is no other MS risk gene with an effect size anywhere near that of the MHC. However, linkage analysis is significantly hampered by reduced power in the face of heterogeneity and requires multiplex families, which also hampers acquiring an appropriate sample size. In contrast, genotyping 500K SNPs allows us to survey a significant amount of the genome (we estimate >70%) directly for allelic or genotypic association. This uses the improved power of association analysis and can also take advantage of the linkage disequilibrium relationships among SNPs to further increase power (e.g. haplotype analysis). Quality control and data analysis are significant challenges. We will initially perform substantial QC checks and analyze the data using both TDT and AFBAC approaches. Multigenic interactions will also be tested using MDR.

• Study Weblinks:
  • International Multiple Sclerosis Consortium
• Study Design:
  • Family/Twin/Trios
• Study Type:
  • Parent-Offspring Trios
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 3002
• Subject Sample Telemetry Report (SSTR)

An MS specialist confirmed an MS diagnosis for collection site participants in this study. The diagnosis of MS was made according to the McDonald criteria after review of all available clinical data. Complete clinical data was available for over 95.0% of patients. Disease course was recorded for patients at entry to study as either relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), or relapsing-progressive (PR) 4. Disability was also assessed at entry with the Expanded Disability Status Scale (EDSS) 5. SPMS was characterized by six months of worsening neurological disability not explained by relapse and measured as a deterioration of either: i) one or more points on the EDSS in patients with an EDSS less than 6, or ii) a one-half point or more for those with an EDSS > 6. PPMS was characterized both by 1) progressive clinical worsening for more than 12 months from symptom onset without any relapses, and 2) abnormal cerebrospinal fluid (CSF) as defined by the presence of two or more oligoclonal bands or elevated IgG index in the CSF. If acute relapses were superimposed on this steadily progressive course, patients were considered to have PRMS. CIS was characterized as the first, well-defined neurological event lasting more than 48 hours, and which involved the optic nerve, spinal cord, brainstem, or cerebellum. In patients presenting with a CIS, the presence of two or more hyper-intense lesions on a T2-weighted MRI sequence was also required for enrollment into the study. A small number of subjects with clinically isolated syndrome (CIS) were included among the US samples used for this study. For the purpose of the analysis, they were treated as cases of "relapsing-remitting" cases of MS since they represent one tail of the distribution of the demyelinating disease spectrum and a majority of them will go on to have a second attack or show evidence of disease progression.

• Primary Phenotype: Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Relapsing-Remitting

• BioProject
• PubMed
• BioSample
• MeSH

• Principal Investigators
  • Alastair Compston, F.Med.Sci, PhD. University of Cambridge School of Clinical Medicine, Cambridge, UK.
  • Stephen L. Hauser, MD. University of California at San Francisco, CA, USA.
  • David A. Hafler, MD. Brigham and Women's Hospital, Boston, MA, USA.
  • Margaret A. Pericak-Vance, PhD. University Of Miami, Miami, FL, USA.
  • Jonathan L. Haines, PhD. Vanderbilt University Medical Center, Nashville, TN, USA.
  • John D. Rioux, Ph.D. Université de Montréal, Montreal, CA.
  • Stephen Sawcer, MB, ChB, PhD. University of Cambridge School of Clinical Medicine, Cambridge, UK.
  • Jorge R. Oksenberg, PhD. University of California at San Francisco, CA, USA.
  • Eric S. Lander, PhD. Broad Institute, Cambridge, MA, USA.
• Co-Investigators
  • Jacob L. McCauley, PhD. Vanderbilt University Medical Center, Nashville, TN, USA.
  • Simon G. Gregory, PhD. Duke University Medical Center, Durham, NC, USA.
  • Mark J. Daly, PhD. Broad Institute, Cambridge, MA, USA.
  • Philip L. De Jager, MD. Brigham and Women's Hospital, Boston, MA, USA.
  • Paul I.W. de Bakker, PhD. Broad Institute, Cambridge, MA, USA.
  • Lisa F. Barcellos, PhD. University of California at Berkeley, Berkeley, CA, USA.
  • Bruce Cree, MD, PhD. University of California at San Francisco, CA, USA.
  • Adrian J. Ivinson, PhD. Harvard Medical School, Boston, MA, USA.
• Institutes
  • University of Cambridge School of Clinical Medicine, Cambridge, UK.
  • University of California at San Francisco, CA, USA.
  • Brigham and Women's Hospital, Boston, MA, USA.
  • University Of Miami, Miami, FL, USA.
  • Vanderbilt University Medical Center, Nashville, TN, USA.
  • Broad Institute, Cambridge, MA, USA.
  • Duke University Medical Center, Durham, NC, USA.
  • University of California at Berkeley, Berkeley, CA, USA.
  • Harvard Medical School, Boston, MA, USA.
• Funding Sources
  • AP-3758-A16. National Multiple Sclerosis Society, New York, NY, USA.
  • RG-2899. National Multiple Sclerosis Society, New York, NY, USA.
  • CA-1001-A14. National Multiple Sclerosis Society, New York, NY, USA.
  • FG-1718-A1. National Multiple Sclerosis Society, New York, NY, USA.
  • NS049477. National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • NS032830. National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • NS26799. National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • AI067152. National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
  • P01-AI039671. National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
  • 76113. Wellcome Trust, London, UK.
  • U54-RR020278-1. National Center for Research Resources, Bethesda, MD, USA.
  • NS2427. National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.