View metadata, citation and similar papers at core.ac.uk brought to you by CORE ARTHRITIS & RHEUMATOLOGY provided by Aberdeen University Research Archive Vol. 66, No. 1, January 2014, pp 24–30 DOI 10.1002/art.38196 © 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Novel Rheumatoid Arthritis Susceptibility Locus at 22q12 Identified in an Extended UK Genome-Wide Association Study Gisela Orozco,1 Sebastien Viatte,1 John Bowes,1 Paul Martin,1 Anthony G. Wilson,2 Ann W. Morgan,3 Sophia Steer,4 Paul Wordsworth,5 Lynne J. Hocking,6 UK Rheumatoid Arthritis Genetics Consortium, Wellcome Trust Case Control Consortium, Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate Consortium, Anne Barton,1 Jane Worthington,1 and Stephen Eyre1 Objective. The number of confirmed rheumatoid extend our previous RA GWAS in a UK cohort, adding arthritis (RA) loci currently stands at 32, but many lines more independent RA cases and healthy controls, with of evidence indicate that expansion of existing genome- the aim of detecting novel association signals for sus- wide association studies (GWAS) enhances the power to ceptibility to RA in a homogeneous UK cohort. detect additional loci. This study was undertaken to Methods. A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, Funding to generate the genome-wide association study data with the extension adding 1,361 cases and 2,334 controls was provided by Arthritis Research UK (grant 17552), Sanofi-Aventis, to the original GWAS data set. The genotype data for all and the European Union Seventh Framework Programme (project POCEMON; FP7-ICT-2007-216088). Genotyping was performed at RA cases were imputed using the Impute program the University of Milan. Dr. Orozco’s work was supported by the version 2. After stringent quality control thresholds Wellcome Trust (Research Career Development Fellowship 095684/ were applied, 3,034 cases and 5,271 controls (1,831,729 Z/11/A). Dr. Viatte’s work was supported by the Swiss Foundation for Medical-Biological Scholarships, which is managed by the Swiss Na- single-nucleotide polymorphisms [SNPs]) were avail- tional Science Foundation (SSMBS grant PASMP3_134380, funded by able for analysis. Association testing was performed a donation from Novartis to the Foundation). using Plink software. 1Gisela Orozco, PhD, Sebastien Viatte, MD, PhD, John Results. Bowes, PhD, Paul Martin, MPhil, Anne Barton, PhD, FRCP, Jane The analyses indicated a suggestive as- Worthington, PhD, Stephen Eyre, PhD: Arthritis Research UK Epi- sociation with susceptibility to RA (P < 0.0001) for 6 demiology Unit, Centre for Musculoskeletal Research, Institute of novel RA loci that have been previously found to be Inflammation and Repair, University of Manchester, and NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester associated with other autoimmune diseases; these 6 Academic Health Science Centre, Manchester, UK; 2Anthony G. SNPs were genotyped in independent samples. Two of Wilson, MB, PhD, FRCP: University of Sheffield, Sheffield, UK; 3Ann the associated loci were validated, one of which was W. Morgan, PhD, FRCP: University of Leeds, Leeds, UK; 4Sophia Steer, PhD, MRCP: Kings College Hospital National Health Service associated with RA at genome-wide levels of significance Foundation Trust, London, UK; 5Paul Wordsworth, MA, MB, BS, in the combined analysis, identifying a novel RA locus at ؋ 10؊9). In addition, most of the 6.9 ؍ FRCP: NIHR Oxford Musculoskeletal Research Unit and Botnar 22q12 (P Research Centre, Nuffield Orthopaedic Centre, Oxford, UK; 6Lynne J. Hocking, PhD: University of Aberdeen, Aberdeen, UK. previously known RA susceptibility loci were confirmed Dr. Martin has received consulting fees, speaking fees, and/or to be associated with RA, and for 16 of the loci, the honoraria from Eli Lilly, Pfizer, AbbVie, and Merck (less than $10,000 strength of the association was increased. each). Conclusion. Address correspondence to Stephen Eyre, PhD, University of This study identified a new RA locus Manchester, Arthritis Research UK Epidemiology Unit, Centre for mapping to 22q12. These results support the notion that Musculoskeletal Research, Institute of Inflammation and Repair, increasing the power of GWAS enhances novel gene Manchester Academic Health Science Centre, Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail: stephen.eyre@ discovery. manchester.ac.uk. Submitted for publication August 22, 2012; accepted in Understanding the genetic component of suscep- revised form September 10, 2013. tibility to rheumatoid arthritis (RA) will increase our 24 NEW RA RISK LOCUS AT 22q12 25 Table 1. Previously confirmed rheumatoid arthritis (RA) loci association results in the original WTCCC association analysis and the expanded UK RA GWAS* WTCCC study Expanded UK RA GWAS Chr. SNP Gene Proxy P OR (95% CI) Proxy P OR (95% CI) 1 rs3890745 TNFRSF14 8.47 ϫ 10Ϫ6 0.82 (0.75–0.89) 1.43 ϫ 10Ϫ6 0.85 (0.79–0.91) 1 rs2476601 PTPN22 rs6679677 2.60 ϫ 10Ϫ25 1.90 (1.68–2.15) 4.87 ϫ 10Ϫ33 1.77 (1.61–1.95) 1 rs11586238 CD2, CD58 4.13 ϫ 10Ϫ4 1.19 (1.08–1.31) rs4271251 6.47 ϫ 10Ϫ3 1.11 (1.03–1.19) 1 rs12746613 FCGR2A 0.04 1.14 (1.01–1.29) 0.03 1.11 (1.01–1.22) 1 rs10919563 PTPRC 0.003 0.82 (0.72–0.94) 7.18 ϫ 10Ϫ5 0.82 (0.74–0.9) 2 rs13031237 REL None rs13031721 0.29 1.04 (0.97–1.11) 2 rs934734 SPRED2 0.10 0.93 (0.86–1.01) 0.11 0.95 (0.89–1.01) 2 rs10865035 AFF3 rs9653442 5.48 ϫ 10Ϫ4 1.16 (1.07–1.26) rs1160542 1.37 ϫ 10Ϫ5 1.15 (1.08–1.23) 2 rs7574865 STAT4 rs11893432 0.02 1.13 (1.02–1.25) rs10181656 6.64 ϫ 10Ϫ4 1.14 (1.06–1.23) 2 rs1980422 CD28 4.80 ϫ 10Ϫ3 1.15 (1.04–1.26) 1.75 ϫ 10Ϫ4 1.15 (1.07–1.24) 2 rs3087243 CTLA4 0.09 0.93 (0.86–1.01) 0.02 0.92 (0.87–0.99) 3 rs13315591 PXK 0.20 1.10 (0.95–1.26) None 4 rs874040 RBPJ None rs6448432 3.88 ϫ 10Ϫ7 1.19 (1.11–1.28) 4 rs6822844 IL2, IL21 None rs62322744 6.42 ϫ 10Ϫ3 1.18 (1.05–1.32) 5 rs6859219 ANKRD55, 5.5 ϫ 10Ϫ6 0.78 (0.70–0.87) None IL6ST 5 rs26232 C5orf30 rs556560 2.46 ϫ 10Ϫ4 0.85 (0.78–0.93) rs556560 9.64 ϫ 10Ϫ5 0.88 (0.82–0.94) 6 rs6910071 HLA–DRB1 rs6457617 3.49 ϫ 10Ϫ79 0.44 (0.40–0.48) rs3763309 1.50 ϫ 10Ϫ124 2.3 (2.14–2.46) 6 rs548234 PRDM1 0.01 1.12 (1.02–1.22) 1.24 ϫ 10Ϫ3 1.12 (1.04–1.19) 6 rs6920220 TNFAIP3 6.11 ϫ 10Ϫ6 1.25 (1.13–1.37) 3.11 ϫ 10Ϫ8 1.23 (1.14–1.32) 6 rs394581 TAGAP 5.86 ϫ 10Ϫ3 0.88 (0.80–0.96) None 6 rs3093023 CCR6 rs6907666 0.05 1.09 (1–1.18) rs3093024 1.88 ϫ 10Ϫ3 1.11 (1.04–1.18) 7 rs10488631 IRF5 rs12531711 0.03 1.16 (1.02–1.31) 3.10 ϫ 10Ϫ3 1.16 (1.05–1.28) 8 rs2736340 BLK 8.01 ϫ 10Ϫ3 1.14 (1.03–1.25) 0.05 1.07 (1–1.15) 9 rs2812378 CCL21 1.14 ϫ 10Ϫ3 1.15 (1.06-1.26) None 9 rs3761847 TRAF1, C5 0.80 0.99 (0.91–1.07) 0.19 1.04 (0.98–1.11) 10 rs2104286 IL2RA 7.06 ϫ 10Ϫ6 0.81 (0.73–0.89) 1.46 ϫ 10Ϫ6 0.84 (0.78–0.9) 10 rs4750316 PRKCQ 5.22 ϫ 10Ϫ5 0.80 (0.72–0.89) 1.55 ϫ 10Ϫ4 0.85 (0.78–0.93) 11 rs540386 TRAF6 0.04 0.88 (0.77–0.99) rs1046864 0.01 0.89 (0.8–0.98) 12 rs1678542 KIF5A 2.81 ϫ 10Ϫ5 0.83 (0.76–0.91) 9.75 ϫ 10Ϫ8 0.83 (0.78–0.89) 20 rs4810485 CD40 0.07 0.91 (0.83–1.01) rs1569723 0.22 0.95 (0.89–1.03) 22 rs3218253 IL2RB 1.88 ϫ 10Ϫ4 1.19 (1.09–1.31) 2.51 ϫ 10Ϫ4 1.15 (1.07–1.23) * WTCCC ϭ Wellcome Trust Case Control Consortium; GWAS ϭ genome-wide association study; Chr. ϭ chromosome; SNP ϭ single-nucleotide polymorphism; OR ϭ odds ratio; 95% CI ϭ 95% confidence interval. knowledge of the disease process and has the potential autoimmune diseases, such as type 1 diabetes (3) and to inform new approaches to disease management. For inflammatory bowel disease (4,5), resulting in a more example, the identification of disease-associated genetic complete picture of the genetic background. variations, which are presumed to cause modified im- In the present study, we used the data set from an mune responses and precede the onset of disease symp- RA GWAS in the UK (6) and increased the sample sizes toms, could inform stratification of patients into more of the RA cases and healthy controls by 75% and 80%, phenotypically homogeneous subgroups and provide respectively. With this extended data set, together with testable hypotheses regarding response to treatment.