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Study Description

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.

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Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

Study Inclusion/Exclusion Criteria

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.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Affymetrix Mapping250K_Nsp 262264 33767 Affymetrix 500K Set comprises Mapping250K_Nsp and Mapping250K_Sty Arrays
Whole Genome Genotyping Affymetrix Mapping250K_Sty 238304 33766 Affymetrix 500K Set comprises Mapping250K_Nsp and Mapping250K_Sty Arrays
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