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High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Abstract

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

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Figure 1: Manhattan plot of association statistics highlighting all autosomal loci associated with rheumatoid arthritis in this study.

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Acknowledgements

We thank J. Barrett and C. Wallace for the SNP selection. We thank the Wellcome Trust Sanger Institute Genotyping Facility, and, in particular, E. Gray, S. Bumpstead, D. Simpkin and H. Blackburn. Genotyping of the UK Rheumatoid Arthritis Genetics samples was supported by the Arthritis Research UK grant reference number 17552 and the Manchester Biomedical Research Centre. This work was made possible by funds from the Arthritis Foundation (S.R., principal investigator) and the US National Institutes Health (K08AR055688 to S.R. and 1R01AR062886-01 to P.I.W.d.B). P. Gilbert prepared the UK samples. Genotyping of the Swedish Umea samples was performed by the SNP&SEQ Technology Platform in Uppsala, which is supported by Uppsala University, Uppsala University Hospital, Science for Life Laboratory–Uppsala and the Swedish Research Council (contracts 80576801 and 70374401). This work was partially supported by the Redes Temáticas de Investigación Cooperativa en Salud (RETICS) Program, RD08/0075 (RIER), from the Instituto de Salud Carlos III, Spain. We acknowledge use of DNA from the UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by the US National Institutes for Health research program grant to the National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. The North American Rheumatoid Arthritis Consortium and analysis of other US patient and control collections at the Feinstein Institute were supported by the US National Institutes of Health RO1-AR-4-4422, NO1-AR-2-2263; NO1-AR1-2256, RO1 AI068759 and RC2AR059092-01, with additional support from the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the family of Robert S. Boas. R.M.P. is supported by grants from the US National Institutes of Health (R01-AR057108, R01-AR056768, U01-GM092691 and R01-AR059648) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund.

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J.W., P.K.G., L.K., S.R., R.M.P. and S. Eyre led the study. S. Eyre, J.B., J.W., R.M.P. and S.R. wrote the paper. J.B., E.S., S.V., A.Z., P.M., P.I.W.d.B., C.I.A., K.M. and D.D. performed the data and statistical analyses. A.L., A.B., L.P., R.E.M.T., T.W.J.H., C.W., G.T., L.F., H.-J.W., L.A., X.H., C.S., S.D., C.C.K., K.K.H., R.A., S. Edkins, S.E.H., C.L., D.S., P.C., S.O.-G., S.S.R., P.D., M.A.G.-G., L.R.-R., L.Ä., J.M. and S.R.-D. contributed primarily to the patient ascertainment, sample collection and/or genotyping. All authors reviewed the final manuscript.

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Correspondence to Jane Worthington.

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The authors declare no competing financial interests.

Additional information

A list of members is provided in the Supplementary Note.

A list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–12, 14 and 15, Supplementary Figures 1–5 and Supplementary Note (PDF 2826 kb)

Supplementary Table 13

eQTL analysis for the lead SNP in the associated rheumatoid arthritis regions (supplied as Excel file) (XLS 95 kb)

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Eyre, S., Bowes, J., Diogo, D. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet 44, 1336–1340 (2012). https://doi.org/10.1038/ng.2462

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