Dataset Information

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

ABSTRACT:

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:

To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls.
To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity.
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.

PROVIDER: phs000171.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.

Baranzini Sergio E SE Wang Joanne J Gibson Rachel A RA Galwey Nicholas N Naegelin Yvonne Y Barkhof Frederik F Radue Ernst-Wilhelm EW Lindberg Raija L P RL Uitdehaag Bernard M G BM Johnson Michael R MR Angelakopoulou Aspasia A Hall Leslie L Richardson Jill C JC Prinjha Rab K RK Gass Achim A Geurts Jeroen J G JJ Kragt Jolijn J Sombekke Madeleine M Vrenken Hugo H Qualley Pamela P Lincoln Robin R RR Gomez Refujia R Caillier Stacy J SJ George Michaela F MF Mousavi Hourieh H Guerrero Rosa R Okuda Darin T DT Cree Bruce A C BA Green Ari J AJ Waubant Emmanuelle E Goodin Douglas S DS Pelletier Daniel D Matthews Paul M PM Hauser Stephen L SL Kappos Ludwig L Polman Chris H CH Oksenberg Jorge R JR

Human molecular genetics 20081114 4

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele ...[more]

PMID: 19010793

Publication: 1/3

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Project description: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 (<a href="http://www.ncbi.nlm.nih.gov/pubmed/11456302" target="_blank">McDonald et al., 2001</a>), 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 (<a href="http://www.ncbi.nlm.nih.gov/pubmed/11456302" target="_blank">McDonald et al., 2001</a>). 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: <ol> <li>To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls.</li> <li>To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity.</li> <li>To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*.</li> </ol> Genotyping Genotyping of the complete dataset was performed at the Illumina facilities using the Sentrix® HumanHap550 BeadChip. *MRI results are not available on dbGaP.

Project description:One of our new major finding among the genes that contributes to MS susceptibility is ICSBP1. The so called disease modifying therapies like interferon-beta (IFN-Î²), possibly acting on the peripheral T-cells, reduce the disease activity and the clinical progression, with a MRI-detectable effect in preventing lesion burden and cerebral atrophy development in RR-MS. It suggests a critical role of peripheral blood mononuclear cells (PBMCs) immune response and modulation in developing inflammation in the brain. We tested the hypothesis that the genetic effect of the susceptible allele ICSBP1 can impact the gene expression profile of molecules belonging to the interferon pathway. We therefore interrogated the PBMC for changes in gene expression profile. We correlate those changes with the minor allele frequency for ICSBP1, performing independent quantitative trait analysis for each treatment category. Expression Quantitative Trait Loci Association with a p value < 0.05 have been used in follow up analysis. The regression coefficient of the Quantitative trait association represents the degree of correlation between the gene expression for each interrogated target gene and the minor allele frequency of the SNP for our gene of interest. This coefficient has been used as input in the subsequent Gene Set Enrichment Analysis performed in a pre-ranked approach. The resulting GSEA-SNP method rests on the assumption that SNPs underlying a disease phenotype might affect genes constituting a signaling pathway or genes with a common regulation. Therefore, GSEA-SNP can facilitate the identification of pathways or of underlying biological mechanisms. We used microarrays to capture gene expression profile of untreated subjects and of subjects under disease modyfing treatment (Interferon Beta and Glatiramer Acetate), in order to correlate gene expression and genotype data and in order to identify sets of genes specifically regulated in the different treatment categories. Experiment Overall Design: Between July 2002 and October 2007, PBMC samples were collected from relapsing-remitting MS subjects and CIS subjects as part of the Comprehensive Longitudinal Investigation of MS at the Brigham & Womenâs Hospital (CLIMB study). We then selected the first time point for each subject with multiple measurements based on an at least three months of treatment criteria. We thereafter analyzed the data for each treament category.

Dataset Information

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

Publications

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.

Similar Datasets

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