Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

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To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

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Figure 1: SNP association plots for ankylosing spondylitis–associated regions.


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We would like to thank all participants, with and without ankylosing spondylitis, who provided the case and control DNA and clinical information necessary for this study. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in subject recruitment. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole Avon Longitudinal Study of Parents And Children (ALSPAC) team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This study was funded by US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and R01-AR046208. Funding was also received from the University of Texas at Houston Clinical and Translational Science Award grant UL1RR024188, Cedars-Sinai General Clinical Research Center grant MO1-RR00425, Intramural Research Program of NIAMS/National Institutes of Health, and Rebecca Cooper Foundation (Australia). This study was funded in part by the Arthritis Research Campaign (UK), by the Wellcome Trust (grant number 076113) and by the Oxford Radcliffe Hospital Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme code A91202). M.A.B. is funded by the National Health and Medical Research Council (Australia). The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC.

Author information

Case assessment and recruitment: L.A.B., M.A.B., J.C.D., L.D., C.F., R.D.I., W.P.M., R.M., E.P., J.D.R., L.S., M.A.S., M.M.W., M.H.W. and B.P.W. Sample processing and genotyping: L.H.A., P.D., T.D., A.D., E.L.D., J.H., D.H., R.J., T.K., R.M., J.J.P., E.P., K.P., A.-M.S., J.T. and X.Z. Gene expression studies: R.D., E.G. and G.P.T. Data analysis: M.A.B., P.D., D.M.E. and P.L. Study design and management committee: M.A.B., J.D.R., M.M.W., M.H.W. and B.P.W. Manuscript preparation: M.A.B., D.M.E., P.L., J.D.R., M.A.S., M.H.W. and B.P.W. ALSPAC control data: P.D., V.K., L.P., S.M.R. and P.W.

Correspondence to John D Reveille or Matthew A Brown.

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Competing interests

M.A.B. is an employee of the University of Queensland, which has applied for patents relating to genes discovered in this study.

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