Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.
To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.
Plenge
Robert M
RM
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. rplenge@partners.org
Cotsapas
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C
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Alkes L
AL
de Bakker
Paul I W
PI
Maller
Julian
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Pe'er
Itsik
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Noel P
NP
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Brendan
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DeFelice
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M
Parkin
Melissa
M
Barry
Rachel
R
Winslow
Wendy
W
Healy
Claire
C
Graham
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RR
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Benjamin M
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Alexander N
AN
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R
Karlson
Elizabeth W
EW
Maher
Nancy
N
Hafler
David A
DA
Lee
David M
DM
Seldin
Michael F
MF
Remmers
Elaine F
EF
Lee
Annette T
AT
Padyukov
Leonid
L
Alfredsson
Lars
L
Coblyn
Jonathan
J
Weinblatt
Michael E
ME
Gabriel
Stacey B
SB
Purcell
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Klareskog
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L
Gregersen
Peter K
PK
Shadick
Nancy A
NA
Daly
Mark J
MJ
Altshuler
David
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D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide