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A Case-Controlled Study for Genotype-Phenotype Associations in Multiple Sclerosis (MS)

This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes.

Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (McDonald et al., 2001), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (McDonald et al., 2001). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).

The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (±5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group.

Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study.

Primary Study Objective:
To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS.

Secondary Study Objectives:

  1. To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls.
  2. To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity.
  3. To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*.

Genotyping
Genotyping of the complete dataset was performed at the Illumina facilities using the Sentrix® HumanHap550 BeadChip.

*MRI results are not available on dbGaP.