Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis
Top Cited Papers
Open Access
- 14 November 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (4) , 767-778
- https://doi.org/10.1093/hmg/ddn388
Abstract
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 frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.Keywords
This publication has 67 references indexed in Scilit:
- GlypicansGenome Biology, 2008
- An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locusProceedings of the National Academy of Sciences, 2007
- TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic CellsImmunity, 2007
- Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variantsNature Genetics, 2007
- Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4PLoS Genetics, 2007
- A second major histocompatibility complex susceptibility locus for multiple sclerosisAnnals of Neurology, 2007
- A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHCNature Genetics, 2006
- PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid feverClinical and Experimental Immunology, 2006
- Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studiesNature Genetics, 2006
- Rating neurologic impairment in multiple sclerosisNeurology, 1983