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Human Molecular Genetics Advance Access published online on November 14, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn388
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Sergio E. Baranzini1,*, Joanne Wang1,*, Rachel A. Gibson2,*, Nicholas Galwey2, Yvonne Naegelin3, Frederik Barkhof4, Ernst-Wilhelm Radue3, Raija L.P. Lindberg3, Bernard Uitdehaag4, Michael R. Johnson2,5, Aspasia Angelakopoulou2, Leslie Hall2, Jill C. Richardson2, Rabinder K. Prinjha2, Achim Gass3, Jeroen J. G. Geurts4, Jolijn Kragt4, Madeleine Sombekke4, Hugo Vrenken4, Pamela Qualley1, Robin R. Lincoln1, Refujia Gomez1, Stacy J. Caillier1, Michaela F. George1, Hourieh Mousavi1, Rosa Guerrero1, Darin T. Okuda1, Bruce A. C. Cree1, Ari Green1, Emmanuelle Waubant1, Douglas S. Goodin1, Daniel Pelletier1, Paul M. Matthews2,5, Stephen L. Hauser1, Ludwig Kappos3, Chris H. Polman4 and Jorge R. Oksenberg1,§

1 Department of Neurology, University of California at San Francisco, US 2 R&D, GlaxoSmithKline 3 Departments of Neurology, Neuroradiology and Biomedicine University Hospital Basel, University of Basel, Switzerland 4 Departments of Neurology and Radiology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 5 Department of Clinical Neurosciences, Imperial College, London, UK

§ To whom correspondence should be addressed at: Department of Neurology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0435, USA. Tel: +1 415 476 1335; Fax: +1 415 476 5229; Email: jorge.oksenberg{at}ucsf.edu

Received September 10, 2008; Revised November 12, 2008; Accepted November 12, 2008

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 (GWAS) performed in a 1,000 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 (MRI) 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.

* Equal contribution


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