Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

Abstract

To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

“…Table 2 compares the minor allele frequencies (MAFs) detected in the NAN control population to that reported in the GWAS. 23 The genotype distribution and MAF for the SNPs detected in the NAN RA cases and controls is shown in Table 3. The data in Table 3 indicate that genotypic distribution for MMEL1-TNFRSF14, FCRL3 and CCL21 differed significantly between controls and RA patients.…”

ANKRD55 and DHCR7 are novel multiple sclerosis risk loci

“…4 --7 rs6859219 located in the ANKRD55 gene was identified in a meta-analysis of RA GWAS, and successfully replicated in the same study. 6 An intronic SNP, rs2301436 in FGFR10P, which flanks the CCR6 gene locus was first identified in Crohn's disease (CD). 8 More recently, rs3093023 in the promoter area of CCR6 at 1.9 kb from the transcription initiation site emerged as risk factor for RA in populations of European ancestry, while rs3093024, also located in the CCR6 promoter at 1.5 kb upstream from rs3093023 and in perfect linkage disequilibrium (LD) with it (D 0 ¼ 1, r 2 ¼ 1) in the European population, was identified as RA risk factor in the Japanese population.…”

“…8 More recently, rs3093023 in the promoter area of CCR6 at 1.9 kb from the transcription initiation site emerged as risk factor for RA in populations of European ancestry, while rs3093024, also located in the CCR6 promoter at 1.5 kb upstream from rs3093023 and in perfect linkage disequilibrium (LD) with it (D 0 ¼ 1, r 2 ¼ 1) in the European population, was identified as RA risk factor in the Japanese population. 6,9 Further evidence for the generalized involvement of the CCR6 gene region in autoimmune disease risk comes from two independent GWAS on vitiligo each of which identified strongly associated SNPs located 30 --175 kb upstream from CCR6. 10,11 The CYP2R1 and DHCR7 loci reached genome-wide significance in two GWAS on vitamin D insufficiency.…”

“…18 A new IL2RA SNP, rs706778, that is located in very close vicinity, that is at only 96 bp from rs2104286, but nevertheless occurs in only partial LD with it (D 0 ¼ 0.89, r 2 ¼ 0. 19), was identified in a RA GWAS, and was included in the present analysis to verify whether it may constitute a novel marker for association with MS. 6 The T allele of rs3024505 located 1.04 kb 3 0 from the polyadenylation site of IL10 has been identified as genetic risk factor in a series of GWAS on ulcerative colitis (UC), CD and systemic lupus erythematosus (SLE). 19 --22 Of note, the alternate C allele of the same SNP was found to be associated with enhanced genetic risk for contracting T1D (see Table 1).…”

“…Finally, PXK was disclosed as risk locus in GWAS on SLE and RA, and the SNP identified in the latter screen was included in the present analysis. 6,26 RESULTS AND DISCUSSION The overall genotyping success rate amounted to 98.4%. Genotypes of all SNPs in cases and controls were in Hardy --Weinberg equilibrium (P410 À2 ).…”