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 & 17 others 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, Jorge R. Oksenberg

Research output: Contribution to journalArticle

321 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)767-778
Number of pages12
JournalHuman Molecular Genetics
Volume18
Issue number4
DOIs
StatePublished - 2009

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Genome-Wide Association Study
Multiple Sclerosis
Single Nucleotide Polymorphism
Phenotype
Heparan Sulfate Proteoglycans
Gene Ontology
Central Nervous System Diseases
Brain
Age of Onset
Gene Frequency
Quality Control
Young Adult
Research Design
Chromosomes
Magnetic Resonance Imaging
Control Groups
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Baranzini, S. E., Wang, J., Gibson, R. A., Galwey, N., Naegelin, Y., Barkhof, F., ... Oksenberg, J. R. (2009). Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Human Molecular Genetics, 18(4), 767-778. https://doi.org/10.1093/hmg/ddn388

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, Vol. 18, No. 4, 2009, p. 767-778.

Research output: Contribution to journalArticle

Baranzini, SE, Wang, J, Gibson, RA, Galwey, N, Naegelin, Y, Barkhof, F, Radue, EW, Lindberg, RLP, Uitdehaag, BMG, Johnson, MR, Angelakopoulou, A, Hall, L, Richardson, JC, Prinjha, RK, Gass, A, Geurts, JJG, Kragt, J, Sombekke, M, Vrenken, H, Qualley, P, Lincoln, RR, Gomez, R, Caillier, SJ, George, MF, Mousavi, H, Guerrero, R, Okuda, DT, Cree, BAC, Green, AJ, Waubant, E, Goodin, DS, Pelletier, D, Matthews, PM, Hauser, SL, Kappos, L, Polman, CH & Oksenberg, JR 2009, 'Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis', Human Molecular Genetics, vol. 18, no. 4, pp. 767-778. https://doi.org/10.1093/hmg/ddn388
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. / Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 4. pp. 767-778.
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AU - Gibson, Rachel A.

AU - Galwey, Nicholas

AU - Naegelin, Yvonne

AU - Barkhof, Frederik

AU - Radue, Ernst Wilhelm

AU - Lindberg, Raija L P

AU - Uitdehaag, Bernard M G

AU - Johnson, Michael R.

AU - Angelakopoulou, Aspasia

AU - Hall, Leslie

AU - Richardson, Jill C.

AU - Prinjha, Rab K.

AU - Gass, Achim

AU - Geurts, Jeroen J G

AU - Kragt, Jolijn

AU - Sombekke, Madeleine

AU - Vrenken, Hugo

AU - Qualley, Pamela

AU - Lincoln, Robin R.

AU - Gomez, Refujia

AU - Caillier, Stacy J.

AU - George, Michaela F.

AU - Mousavi, Hourieh

AU - Guerrero, Rosa

AU - Okuda, Darin T.

AU - Cree, Bruce A C

AU - Green, Ari J.

AU - Waubant, Emmanuelle

AU - Goodin, Douglas S.

AU - Pelletier, Daniel

AU - Matthews, Paul M.

AU - Hauser, Stephen L.

AU - Kappos, Ludwig

AU - Polman, Chris H.

AU - Oksenberg, Jorge R.

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