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

Abstract

To identify new genetic risk factors for rheumatoid arthritis, we conducted 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 in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 × 10−8) in an 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 associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis 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 genuine rheumatoid arthritis risk alleles.

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Figure 1: Associations with rheumatoid arthritis risk across four loci.
Figure 2: Previously validated autoimmune SNPs tested in our replication study.

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Acknowledgements

R.M.P. is supported by grants from the US National Institutes of Health (NIH) (R01-AR057108, R01-AR056768 and U54 RR020278), a private donation from the Fox Trot Fund, the William Randolph Hearst Fund of Harvard University, the American College of Rheumatology 'Within Our Reach' campaign and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. S.R. is supported by an NIH Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. F.A.S.K. is supported by an EMBO-UNESCO L'Oreal Fellowship. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The BRASS Registry is supported by a grant from Crescendo and Biogen-Idec. EIRA is supported by grants from the Swedish Medical Research council, the Swedish Council for Working Life and Social Research, King Gustaf V's 80-year foundation, the Swedish Rheumatism Foundation, Stockholm County Council, from Vinnova and the insurance company AFA. NARAC is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). L.A.C. is supported by the NIH (R01 AI065841 and 5-M01-RR-00079). The Nurses Health Study is supported by NIH grants P01 CA87969, CA49449, CA67262, CA50385, AR049880-06 and AR47782. This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the US National Institutes of Health. This research was also supported in part by grants to K.A.S. from the Canadian Institutes for Health Research (MOP79321 and IIN-84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. Genotyping of United Kingdom Rheumatoid Arthritis Genetics samples was supported by the Arthritis Research campaign arc grant reference number 17552 and by the Manchester Biomedical Research Centre and Manchester Academy of Health Sciences. C.W. was funded by the Netherlands Organization for Scientific Research (VICI grant 918.66.620). We acknowledge the help of B.A.C. Dijkmans, D. van Schaardenburg, A. Salvador Peña, P.L. Klarenbeek, Z. Zhang, M.T. Nurmohamed, W.F. Lems, R.R. J. van de Stadt, W.H. Bos, J. Ursum, M.G.M. Bartelds, D.M. Gerlag, M.G.H. van der Sande, C.A. Wijbrandts and M.M.J. Herenius in gathering Genetics Network Rheumatology Amsterdam subject samples and data. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of genotype data from their healthy controls in our study. The MIGen study was funded by the US National Institutes of Health and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiological Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank J. Seddon, Progression of AMD Study, Age-Related Macular Degeneration (AMD) Registry Study, Family Study of AMD, The US Twin Study of AMD and the Age-Related Eye Disease Study (AREDS) for use of genotype data from their healthy controls in our study. We thank D. Hafler and the Multiple Sclerosis Collaborative for use of genotype data from their healthy controls recruited at Brigham and Women's Hospital.

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Study design: R.M.P., S.R., E.A.S. Analysis: E.A.S. (lead), S.R., F.A.S.K., R.C. Sample procurement and data generation: J.W., K.A.S., P.K.G., L.K., N.A.S., M.E.W., C.W., M.J.H.C., N.d.V., P.P.T., E.W.K., R.E.M.T., T.W.J.H., A.B.B. (leads); E.F.R., G.X., S.E., B.P.T., Y.L., A.Z., A.H., C.G., L.A., C.I.A., K.G.A., A.B., J.B., E.B., N.P.B., J.J.C., J. Coblyn, K.H.C., L.A.C., J.B.A.C., J. Cui, P.I.W.d.B., P.L.D.J., B.D., P.E., E.F., P.H., L.J.H., D.L.K., X.K., A.T.L., X.L., P.M., A.W.M., L.P., M.D.P., T.R.D.J.R., D.M.R., M.S., M.F.S., S.S., W.T., A.H.M.v.d.H.-v.M., I.E.v.d.H.-B., C.E.v.d.S., P.L.C.M.v.R., A.G.W., G.J.W., B.P.W., BIRAC and YEAR consortia. Writing: R.M.P., E.A.S. (leads); S.R., F.A.S.K. (primary contributors); J.W., K.A.S., P.K.G., L.K., N.A.S., M.E.W., C.W., M.J.H.C., N.d.V., P.P.T., E.W.K., R.E.M.T., T.W.J.H., A.B.B., E.F.R., G.X., S.E., B.P.T., Y.L., A.Z., A.H., C.G., L.A., C.I.A., K.G.A., A.B., J.B., E.B., N.P.B., J.J.C., J. Coblyn, K.H.C., L.A.C., J.B.A.C., J. Cui, P.I.W.d.B., P.L.D.J., B.D., P.E., E.F., P.H., L.J.H., D.L.K., X.K., A.T.L., X.L., P.M., A.W.M., L.P., M.D.P., T.R.D.J.R., D.M.R., M.S., M.F.S., S.S., W.T., A.H.M.v.d.H.-v.M., I.E.v.d.H.-B., C.E.v.d.S., P.L.C.M.v.R., A.G.W., G.J.W., B.P.W.

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Correspondence to Robert M Plenge.

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Stahl, E., Raychaudhuri, S., Remmers, E. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42, 508–514 (2010). https://doi.org/10.1038/ng.582

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