Risk alleles for multiple sclerosis identified by a genomewide study.
BACKGROUND
Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.


METHODS
We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.


RESULTS
A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)).


CONCLUSIONS
Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.
Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, USA.
David A
DA
Hafler
Alastair
A
Compston
Stephen
S
Sawcer
Eric S
ES
Lander
Mark J
MJ
Daly
Philip L
PL
De Jager
Paul I W
PI
de Bakker
Stacey B
SB
Gabriel
Daniel B
DB
Mirel
Adrian J
AJ
Ivinson
Margaret A
MA
Pericak-Vance
Simon G
SG
Gregory
John D
JD
Rioux
Jacob L
JL
McCauley
Jonathan L
JL
Haines
Lisa F
LF
Barcellos
Bruce
B
Cree
Jorge R
JR
Oksenberg
Stephen L
SL
Hauser
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006684:HLA-DR Antigens / Q000235:genetics*; D059805:HLA-DR alpha-Chains; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit