Overview

A genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication. Genotyping of the studies were performed on Illumina, Affymetrix, Sequenom iPlex,Kinetic PCR, Biotrove OpenArray platforms. Data processing and quality control filtering were performed in PLINK. Imputation was conducted on GWAS genotype data for each GWAS collection separately, using the IMPUTE software and haplotype-phased HapMap Phase 2 European CEU founders as a reference panel. 2.56 million (2,554,714) SNPS  were available for meta-analysis. SNPTEST software was used for logistic regression after Imputation. 34 SNPs were selected for replication in 6,768 cases and 8,806 controls. 10 loci were found to have convincing evidence of association with risk of autoantibody-positive rheumatoid arthritis, 7 of which represent new risk loci, in which risk alleles were identified at genome-wide significance (P < 5 × 10−8).  The study also identifies  additional 11 SNPs with highly suggestive associations with rheumatoid arthritis(defined as P<0.05 in replication samples). The remaining 13 SNPs failed to replicate significantly.

Study Type
Whole Genome Association Study
Samples
GroupPhenotypePopulationCasesControlsFamiliesTrios
DiscoveryRA553920169--
ReplicationRA67688806--
Exclusion Criteria

Sample Exclusion:

Rheumatoid arthritis cases were limited to only individuals who either were anti-CCP positive or, if anti-CCP status data were missing, were rheumatoid factor positive.
 
Duplicated individuals from genetically identical samples from the same country were removed(identified using available SNP data from this and previous studies)
 
SNP Exclusion:
 
For GWAS meta-analysis, quality control steps included filtering SNPs and individuals with >5% missing data, followed by filtering SNPs with MAF <1% and a χ2 test of Hardy-Weinberg equilibrium (HWE) PHWE < 10−6. For the WTCCC collection, genotyped on the older Affymetrix 500K platform,  more stringent quality control criteria was implemented (>1% missing data,MAF < 1% and PHWE < 10−5). 
 
For replication (in each collection), quality control exclusion criteria for SNPs were 10% missing data, MAF < 1% and PHWE < 10−3. If a given SNP failed in genotyping or quality control in a collection, a proxy SNP (r2 > 0.8) with the least missing data (if available) was used instead.

Study Association

RegionLocationGene(s)MarkerAlleleMAFP ValueOdds Ratio
1q21.3chr1:154398462-154694215IL6R  rs7543174T > C0.1601.20e-05C1.13 (1.06-1.15)D
1q24.2chr1:167192336-167474186CD247  rs840016C > T0.4201.60e-06C1.11 (1.06-1.15)D
2p14chr2:65170461-65489960SPRED2  rs934734A > G0.4905.30e-10C1.13 (1.09-1.17)D
2q11.2chr2:99927805-100425222AFF3  rs11676922A > T0.4601.00e-14C1.12 (1.10-1.18)D
3p14.3chr3:58563920-58615320PXK  rs13315591T > C0.0904.60e-08C1.29 (1.12-1.28)D
4p15.2chr4:26026886-26130530RBPJ  rs874040G > C0.3001.00e-16C1.14 (1.12-1.20)D
4q27chr4:122017479-122644147IL21  IL2  rs13119723A > G0.1506.80e-07C1.12 (1.08-1.19)D
5q11.2chr5:56119129-56152598IL6ST  ANKRD55  rs6859219C > A0.2109.60e-12C1.28 (1.16-1.3)D
5q21.1chr5:102699259-103413530C5orf30  rs26232C > T0.3204.10e-08C1.14 (1.06-1.15)D
6q27chr6:166935019-167134466RP11-517H2.6  CCR6  rs3093023G > A0.4301.50e-11C1.13 (1.08-1.16)D
7q32.1chr7:128911686-129137466IRF5  rs10488631T > C0.1104.20e-11C1.19 (1.14-1.28)D
9p13.3chr9:34680856-34996017CCL21  rs951005A > G0.1603.90e-10C1.19 (1.11-1.22)D
10p11.22chr10:30812612-31191395ZEB1  rs2793108T > C0.4301.40e-05C1.08 (1.04-1.11)D
10p15.1chr10:5988280-6135719IL2RA  rs11594656T > A0.2501.00e-04C1.11 (1.04-1.12)D
10p15.1chr10:5988280-6129961IL2RA  rs706778C > T0.4001.40e-11C1.14 (1.09-1.16)D
12q24.12chr12:111278572-112592683SH2B3  rs3184504T > C0.4906.00e-06C1.08 (1.04-1.11)D
14q24.3chr14:75476220-75564299BATF  rs7155603A > G0.1901.10e-07C1.16 (1.09-1.20)D
16p11.2chr16:28283985-29021481NFATC2IP  CD19  rs8045689T > C0.3002.40e-05C1.14 (1.05-1.13)D
17q12chr17:39226421-40083963IKZF3  rs2872507G > A0.4709.40e-07C1.10 (1.05-1.13)D
21q22.3chr21:42389309-42458550UBASH3A  rs11203203G > A0.3703.80e-06C1.11 (1.05-1.13)D
22q11.21chr22:21454896-21649639UBE2L3  rs5754217G > T0.1904.80e-05C1.10 (1.05-1.13)D

Criteria

GDXHsS00014 meets the following criteria:

Criteria Name
Details
Disease Tags
Study for a Disease 

Publications

PMIDTitleFirst AuthorJournalDisease(s)Date