Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.
Authors
Sergio E. Baranzini, University of California, San Francisco
Joanne Wang, University of California, San Francisco
Rachel A. Gibson, GlaxoSmithKline
Nicholas Galwey, GlaxoSmithKline
Yvonne Naegelin, University of Basel
Frederik Barkhof, Vrije Universiteit Medical Centre, Amsterdam
Ernst-Wilhelm Radue, University of Basel
Raija L. P. Lindberg, University of Basel
Bernard M. G. Uitdehaag, Vrije Universiteit Medical Centre, Amsterdam
Michael R. Johnson, GlaxoSmithKline
Aspasia Angelakopoulou, GlaxoSmithKline
Leslie Hall, GlaxoSmithKline
Jill C. Richardson, GlaxoSmithKline
Rab K. Prinjha, GlaxoSmithKline
Achim Gass, Vrije Universiteit Medical Centre, Amsterdam
Jeroen J. G. Geurts, Vrije Universiteit Medical Centre, Amsterdam
Jolijn Kragt, Vrije Universiteit Medical Centre, Amsterdam
Madeleine Sombekke, Vrije Universiteit Medical Centre, Amsterdam
Hugo Vrenken, Vrije Universiteit Medical Centre, Amsterdam
Pamela Qualley, University of California, San Francisco
Robin R. Lincoln, University of California, San Francisco
Refujia Gomez, University of California, San Francisco
Stacy J. Caillier, University of California, San Francisco
Michaela George, University of California, San FranciscoFollow
Hourieh Mousavi, University of California, San Francisco
Rosa Guerrero, University of California, San Francisco
Darin T. Okuda, University of California, San Francisco
Bruce A. C. Cree, University of California, San Francisco
Ari J. Green, University of California, San Francisco
Emmanuelle Waubant, University of California, San Francisco
Douglas S. Goodin, University of California, San Francisco
Daniel Pelletier, University of California, San Francisco
Paul M. Matthews, GlaxoSmithKline
Stephen L Hauser, University of California, San Francisco
Ludwig Kappos, University of Basel
Chris H. Polman, Vrije Universiteit Medical Centre, Amsterdam
Jorge R. Oksenberg, University of California, San Francisco
Department
Global Public Health
Document Type
Published Article
Source
Human Molecular Genetics
Publication Date
2-15-2009
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.
