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.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to play an important role in genetic susceptibility to common disease. To address this we undertook a large direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500bp. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell-lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease, IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis, and type 1 diabetes, and TSPAN8 for type 2 diabetes, though in each case the locus had previously been identified in SNP-based studies, reflecting our observation that the majority of common CNVs which are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs which can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10 -5 -5 × 10 -7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10 -8 ) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α-induced protein 3 (TNFAIP3).The WTCCC genome-wide association screen (GWA) of 1,860 rheumatoid arthritis cases and 2,938 healthy controls confirmed association with SNPs within the HLA region and the PTPN22 gene (P < 1 × 10 -7 ; ref. 1). Nine other loci showed strong evidence for association (P = 1 × 10 -5 -5 × 10 -7 ). SNPs at these loci were genotyped in an independent cohort of 5,063 rheumatoid arthritis cases and 3,849 healthy controls (Supplementary Methods and Supplementary Table 1 Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts www.sequenom.com), to establish whether they are genuinely associated with the disease. In this cohort, we had 80% power to detect most of the effect sizes reported in the initial study at P < 0.05 (Supplementary Table 2 online). We selected ten SNPs for genotyping; these included the known rheumatoid arthritis susceptibility variant rs2476601, mapping to the PTPN22 gene, and nine previously unknown SNPs identified by the WTCCC study1. A Bonferroni correction of 9 was applied to account for the previously unknown loci investigated, resulting in a P value threshold of P < 0.006 for claims of significance in this validation study. We regarded SNPs validated at P values between 0.05 and 0.006 as suggestive evidence.We detected strong association with the rheumatoid arthritis-causing SNP in the PTPN22 gene (rs2476601), as expected (odds ratio (OR) = 1.53, 95% CI = 1.39-1.68, trend P = 2.0 × 10 -18 ). This was not a completely independent replication, as association of rheumatoid arthritis with this locus has been reported in previous studies using some of the same samples included in the current study2-4. However, it confirmed the suitability of this cohort for validation studies. Of the nine newly identified SNPs tested, rs6920220 (G > A) showed association with rheumatoid arthritis in this cohort (OR for minor allele = 1.23, 95% CI = 1.15-1.33, trend P = 1.1 × 10 -8 ) (Table 1). For this SNP, the allele frequencies were similar across control groups tested in the WTCCC study and the healthy controls tested here (minor allele frequency (MAF) 0.22 and 0.21, respectively). We therefore undertook a combined analysis of the WTCCC data and the validation data, and we obtained strong statistical evidence for association between this SNP and rheumatoid arthritis (OR = 1.22, 95% CI = 1.15-1.29, trend P = 3.6 × 10 -12