Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.
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.
Baranzini
Sergio E
SE
Department of Neurology, University of California, San Francisco, CA 94143-0435, USA.
Wang
Joanne
J
Gibson
Rachel A
RA
Galwey
Nicholas
N
Naegelin
Yvonne
Y
Barkhof
Frederik
F
Radue
Ernst-Wilhelm
EW
Lindberg
Raija L P
RL
Uitdehaag
Bernard M G
BM
Johnson
Michael R
MR
Angelakopoulou
Aspasia
A
Hall
Leslie
L
Richardson
Jill C
JC
Prinjha
Rab K
RK
Gass
Achim
A
Geurts
Jeroen J G
JJ
Kragt
Jolijn
J
Sombekke
Madeleine
M
Vrenken
Hugo
H
Qualley
Pamela
P
Lincoln
Robin R
RR
Gomez
Refujia
R
Caillier
Stacy J
SJ
George
Michaela F
MF
Mousavi
Hourieh
H
Guerrero
Rosa
R
Okuda
Darin T
DT
Cree
Bruce A C
BA
Green
Ari J
AJ
Waubant
Emmanuelle
E
Goodin
Douglas S
DS
Pelletier
Daniel
D
Matthews
Paul M
PM
Hauser
Stephen L
SL
Kappos
Ludwig
L
Polman
Chris H
CH
Oksenberg
Jorge R
JR
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
C106228:GPC5 protein, human; D053673:Glypicans