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

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

In: Human Molecular Genetics, 2009, vol. 18, no. 4, p. 767-778

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    Title
    • Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis
    Author
    • Baranzini, Sergio E.. Department of Neurology, University of California, San Francisco, USA
    • Wang, Joanne. Department of Neurology, University of California, San Francisco, USA
    • Gibson, Rachel A.. R&D, GlaxoSmithKline, UK and USA
    • Galwey, Nicholas. R&D, GlaxoSmithKline, UK and USA
    • Naegelin, Yvonne. Department of Neurology, University Hospital Basel, University of Basel, Switzerland
    • Barkhof, Frederik. Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Radue, Ernst-Wilhelm. Department of Neuroradiology, University Hospital Basel, University of Basel, Switzerland
    • Lindberg, Raija L.P.. Department of Neurology, University Hospital Basel, University of Basel, Switzerland
    • Uitdehaag, Bernard M.G.. Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Johnson, Michael R.. R&D, GlaxoSmithKline, UK and USA
    • Angelakopoulou, Aspasia. R&D, GlaxoSmithKline, UK and USA
    • Hall, Leslie. R&D, GlaxoSmithKline, UK and USA
    • Richardson, Jill C.. R&D, GlaxoSmithKline, UK and USA
    • Prinjha, Rab K.. R&D, GlaxoSmithKline, UK and USA
    • Gass, Achim. Department of Neuroradiology, University Hospital Basel, University of Basel, Switzerland
    • Geurts, Jeroen J.G.. Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Kragt, Jolijn. Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Sombekke, Madeleine. Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Vrenken, Hugo. Department of Physics and Medical Technology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Qualley, Pamela. Department of Neurology, University of California, San Francisco, USA
    • Lincoln, Robin R.. Department of Neurology, University of California, San Francisco, USA
    • Gomez, Refujia. Department of Neurology, University of California, San Francisco, USA
    • Caillier, Stacy J.. Department of Neurology, University of California, San Francisco, USA
    • George, Michaela F.. Department of Neurology, University of California, San Francisco, USA
    • Mousavi, Hourieh. Department of Neurology, University of California, San Francisco, USA
    • Guerrero, Rosa. Department of Neurology, University of California, San Francisco, USA
    • Okuda, Darin T.. Department of Neurology, University of California, San Francisco, USA
    • Cree, Bruce A. C.. Department of Neurology, University of California, San Francisco, USA
    • Green, Ari J.. Department of Neurology, University of California, San Francisco, USA
    • Waubant, Emmanuelle. Department of Neurology, University of California, San Francisco, USA
    • Goodin, Douglas S.. Department of Neurology, University of California, San Francisco, USA
    • Pelletier, Daniel. Department of Neurology, University of California, San Francisco, USA
    • Matthews, Paul M.. R&D, GlaxoSmithKline, UK and USA
    • Hauser, Stephen L.. Department of Neurology, University of California, San Francisco, USA
    • Kappos, Ludwig. Department of Neurology, University Hospital Basel, University of Basel, Switzerland
    • Polman, Chris H.. Department of Radiology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
    • Oksenberg, Jorge R.. Department of Neurology, University of California, San Francisco, USA
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Human Molecular Genetics, 2009, vol. 18, no. 4, p. 767-778. Oxford University Press
    Other Version
    Classification
    • Health
    OAI-PMH Identifier
    • oai:doc.rero.ch:300053
    Summary
    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