title: Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.
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.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143-0435, USA.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Galwey
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Naegelin
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.forename: Raija L P
authors.initials: RL
authors.lastname: Lindberg
authors.forename: Bernard M G
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Aspasia
authors.initials: A
authors.lastname: Angelakopoulou
authors.forename: Leslie
authors.initials: L
authors.lastname: Hall
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Achim
authors.initials: A
authors.lastname: Gass
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
authors.forename: Jolijn
authors.initials: J
authors.lastname: Kragt
authors.forename: Madeleine
authors.initials: M
authors.lastname: Sombekke
authors.forename: Hugo
authors.initials: H
authors.lastname: Vrenken
authors.forename: Pamela
authors.initials: P
authors.lastname: Qualley
authors.forename: Robin R
authors.initials: RR
authors.lastname: Lincoln
authors.forename: Refujia
authors.initials: R
authors.lastname: Gomez
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.forename: Michaela F
authors.initials: MF
authors.lastname: George
authors.forename: Hourieh
authors.initials: H
authors.lastname: Mousavi
authors.forename: Rosa
authors.initials: R
authors.lastname: Guerrero
authors.forename: Darin T
authors.initials: DT
authors.lastname: Okuda
authors.forename: Bruce A C
authors.initials: BA
authors.lastname: Cree
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Green
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Waubant
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
authors.forename: Daniel
authors.initials: D
authors.lastname: Pelletier
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C106228:GPC5 protein, human; D053673:Glypicans