Journal Article

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

Sergio E. Baranzini, Joanne Wang, Rachel A. Gibson, Nicholas Galwey, Yvonne Naegelin, Frederik Barkhof, Ernst-Wilhelm Radue, Raija L.P. Lindberg, Bernard M.G. Uitdehaag, Michael R. Johnson, Aspasia Angelakopoulou, Leslie Hall, Jill C. Richardson, Rab K. Prinjha, Achim Gass, Jeroen J.G. Geurts, Jolijn Kragt, Madeleine Sombekke, Hugo Vrenken, Pamela Qualley, Robin R. Lincoln, Refujia Gomez, Stacy J. Caillier, Michaela F. George, Hourieh Mousavi, Rosa Guerrero, Darin T. Okuda, Bruce A. C. Cree, Ari J. Green, Emmanuelle Waubant, Douglas S. Goodin, Daniel Pelletier, Paul M. Matthews, Stephen L. Hauser, Ludwig Kappos, Chris H. Polman and Jorge R. Oksenberg

in Human Molecular Genetics

Volume 18, issue 4, pages 767-778
Published in print February 2009 | ISSN: 0964-6906
Published online November 2008 | e-ISSN: 1460-2083 | DOI:
Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

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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.

Journal Article.  5890 words.  Illustrated.

Subjects: Genetics and Genomics

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