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Human Molecular Genetics Advance Access originally published online on November 14, 2008
Human Molecular Genetics 2009 18(4):767-778; 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,{dagger}, Joanne Wang1,{dagger}, Rachel A. Gibson2,{dagger}, Nicholas Galwey2, Yvonne Naegelin3, Frederik Barkhof4, Ernst-Wilhelm Radue5, Raija L.P. Lindberg3, Bernard M.G. Uitdehaag6, Michael R. Johnson2,7, Aspasia Angelakopoulou2, Leslie Hall2, Jill C. Richardson2, Rab K. Prinjha2, Achim Gass5, Jeroen J.G. Geurts4, Jolijn Kragt6, Madeleine Sombekke6, Hugo Vrenken8, 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 J. Green1, Emmanuelle Waubant1, Douglas S. Goodin1, Daniel Pelletier1, Paul M. Matthews2,7, Stephen L. Hauser1, Ludwig Kappos3, Chris H. Polman4 and Jorge R. Oksenberg1,*

1 Department of Neurology, University of California, San Francisco, USA 2 R&D, GlaxoSmithKline, UK and USA 3 Department of Neurology, University Hospital Basel, University of Basel, Switzerland 4 Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 5 Department of Neuroradiology, University Hospital Basel, University of Basel, Switzerland 6 Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 7 Department of Clinical Neurosciences, Imperial College, London, UK 8 Department of Physics and Medical Technology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands

* To whom correspondence should be addressed at: Department of Neurology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0435, USA. Tel: +1 4154761335; Fax: +1 4154765229; Email: jorge.oksenberg{at}ucsf.edu

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.

{dagger}The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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