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ABSTRACT Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to _HLA-B*27_ alleles, 12 loci have previously been

identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina

Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12

additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in

peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and

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129 NOVEL ASSOCIATIONS IN 11 AUTOIMMUNE DISEASES Article Open access 03 November 2023 TUTORIAL: A STATISTICAL GENETICS GUIDE TO IDENTIFYING HLA ALLELES DRIVING COMPLEX DISEASE Article 26

July 2023 GENOME-WIDE ASSOCIATION STUDY IDENTIFIES SJÖGREN’S RISK LOCI WITH FUNCTIONAL IMPLICATIONS IN IMMUNE AND GLANDULAR CELLS Article Open access 27 July 2022 REFERENCES * Braun, J.,

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spondylitis and healthy individuals who provided the DNA and clinical information necessary for this study. The Wellcome Trust Case Control Consortium 2 project is funded by the Wellcome

Trust (083948/Z/07/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the

UK National Blood Service controls, funded by the Wellcome Trust. We thank J.C. Barrett for contributing the design of the Immunochip and for helpful analytical discussion, as well as E.

Gray, S. Bumpstead, D. Simpkin and the staff of the Wellcome Trust Sanger Institute Sample Management and Genotyping teams for their genotyping and analytical contributions. The

Australo-Anglo-American Spondyloarthritis Consortium (TASC) study was funded by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and

R01-AR046208. Funding was also received from University of Texas at Houston Clinical and Translational Science Award (CTSA) UL1RR024188, Cedars-Sinai General Clinical Research Center (GCRC)

grant MO1-RR00425, the Intramural Research Program, NIAMS, US National Institutes of Health and the Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis

Research UK (grants 19536 and 18797), by the Wellcome Trust (grant 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme

A91202). We thank A. Harrison (University of Otago) for his contribution to the New Zealand ankylosing spondylitis cohort. H.X. was funded by National Natural Science Foundation of China

grants 81020108029 and 30872339. Portuguese sample collection was performed by COnhecer a Realidade PORtuguesa sobre a Espondilite Anquilosante (CORPOREA Study Group), coordinated by

F.M.P.-S. and supported by Bolsa Investigação da Sociedade Portuguesa de Reumatologia/Schering-Plough 2007. The Spanish ankylosing spondylitis case collection was supported by Spanish grant

FICYT PC-10-70-Fondos FEDER European Union. The Spondyloarthritis Research Consortium of Canada (SPARCC) was funded by a National Research Initiative Award from the Arthritis Society

(Canada). French sample collection was performed by the Groupe Française d'Etude Génétique des Spondylarthrites, coordinated by R. Said-Nahal and funded by Agence Nationale de Recherche

GEnetics, Microbiota, Inflammation and Spondyloarthritis (GEMISA) grant ANR-10-MIDI-0002. We thank the Norwegian Bone Marrow Donor registry for providing data from healthy Norwegian

controls. W.P.M. is a Medical Scientist of Alberta Innovates–Health Solutions. The Psoriatic Arthritis Program is supported by the Krembil Foundation and the Arthritis Society. P.C.R. is

funded by the National Health and Medical Research Council (Australia) (NHMRC) and Arthritis Australia. J.Y. is supported by NHMRC grants 613672 and 1011506. M. Ward is supported by the

Intramural Research Program, NIAMS, US National Institutes of Health. D.E. is supported by the research council of Ghent University and by the Fund for Scientific Research Flanders. M.A.B.

is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship, and support for this study was received from a National Health and Medical

Research Council (Australia) program grant (566938) and project grant (569829) and from the Australian Cancer Research Foundation and the Rebecca Cooper Medical Research Foundation. We thank

A. Gardiner and the Brisbane Convention and Exhibition Centre for their assistance in preparing the manuscript. We are also very grateful for the invaluable support received from the

National Ankylosing Spondylitis Society (UK) and the Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for subject recruitment was

provided by the NIHR Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and by an unrestricted educational grant from Abbott Laboratories.

AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia Adrian Cortes, Johanna Hadler, 

Philip C Robinson, Paul Leo, Katie Cremin, Karena Pryce, Jessica Harris, Linda A Bradbury, Tony J Kenna, Jian Yang & Matthew A Brown * National Institute for Health Research (NIHR)

Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK Jenny P Pointon, Tugce Karaderi, Louise Appleton, Claire Farrah, Jonathan Lau, Paul

Bowness & Bryan Paul Wordsworth * Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea Seunghun Lee, Kyung Bin Joo & Tae-Hwan Kim

* Department of Medicine, Division of Rheumatology, Eulji University Hospital, Daejeon, Republic of Korea Seung-Cheol Shim * Department of Medicine/Rheumatology, Cedars-Sinai Medical Center,

Los Angeles, California, USA Michael Weisman * National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA Michael Ward

* Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA Xiaodong Zhou & John D Reveille * Institut Cochin, Université

Paris–Descartes, Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherhce (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France

Henri-Jean Garchon, Gilles Chiocchia & Maxime Breban * Division of Rheumatology, Ambroise Paré Hospital, Assistance Publique–Hôpitaux de Paris, Versailles-Saint-Quentin en Yvelines

University, Boulogne-Billancourt, France Henri-Jean Garchon & Maxime Breban * University Hospital North Norway, Tromso, Norway Johannes Nossent * Division of Medicine, Royal Darwin

Hospital, Darwin, Northern Territory, Australia Johannes Nossent * Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway Benedicte A Lie * Department

of Immunology, Oslo University Hospital, Oslo, Norway Benedicte A Lie * Department of Rheumatology, University Hospital Oslo, Oslo, Norway Øystein Førre * Centre for Vascular Prevention,

Danube-University Krems, Krems, Austria Jaakko Tuomilehto * Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland Jaakko Tuomilehto * King Abdulaziz

University, Jeddah, Saudi Arabia Jaakko Tuomilehto * Paijat-Hame Central Hospital, Lahti, Finland Kari Laiho * Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second

Military Medical University, Shanghai, China Lei Jiang, Yu Liu, Xin Wu & Huji Xu * Department of Rheumatology, Ghent University Hospital, Ghent, Belgium Dirk Elewaut * Department of

Rheumatology, Hospital General de México, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, México Ruben Burgos-Vargas * Department of Medicine, Dunedin School of

Medicine, University of Otago, Dunedin, New Zealand Simon Stebbings * Division of Rheumatology, Toronto Western Hospital, Toronto, Ontario, Canada Nigil Haroon & Robert D Inman *

Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland, Australia Manuel A Ferreira * Rheumatology Department, Hospital Puerta de Hierro, Madrid, Spain Juan

Mulero * Rheumatology Department, Complejo Hospitalario La Coruña, Instituto de Investigación Biomédica A Coruña (INIBIC), La Coruña, Spain Jose Luis Fernandez-Sueiro * Rheumatology

Department, Hospital Marqués de Valcecilla, Instituto de Formación e Investigación Marqués de Valcecillas (IFIMAV), Santander, Spain Miguel A Gonzalez-Gay * Department of Immunology,

Asturias Central University Hospital, Oviedo, Spain Carlos Lopez-Larrea * Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain Carlos Lopez-Larrea * Wellcome Trust Sanger Institute,

Cambridge, UK Panos Deloukas * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Peter Donnelly * Department of Rheumatology, Norfolk and Norwich University

Hospital, Norwich, UK Karl Gafney * Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK Hill Gaston * Division of Rheumatology, University of Toronto,

Toronto, Ontario, Canada Dafna D Gladman * Toronto Western Research Institute, Toronto, Ontario, Canada Dafna D Gladman * Psoriatic Arthritis Program, University Health Network, Toronto,

Ontario, Canada Dafna D Gladman * Memorial University of Newfoundland, St. John's, Newfoundland, Canada Proton Rahman * Department of Medicine, University of Alberta, Edmonton, Alberta,

Canada Walter P Maksymowych * Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands J Bart A

Crusius * Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands Irene E van der Horst-Bruinsma * Department of Medicine, Division of Allergy, Immunology,

Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan Chung-Tei Chou * School of Medicine, National Yang-Ming University, Taipei, Taiwan Chung-Tei Chou * Division of Rheumatology,

Spondyloarthropathy Group, Hospital Militar Central, Universidad de La Sabana, Bogotá, Colombia., Raphael Valle-Oñate & Consuelo Romero-Sánchez * Helgelandssykehuset, Mo i Rana, Norway

Inger Myrnes Hansen * Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal Fernando M Pimentel-Santos * Department of

Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway Vibeke Videm * Department of Immunology and Transfusion

Medicine, Trondheim University Hospital, Trondheim, Norway Vibeke Videm * Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada,

Spain Javier Martin * Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Bristol, UK David M Evans CONSORTIA

INTERNATIONAL GENETICS OF ANKYLOSING SPONDYLITIS CONSORTIUM (IGAS) * Adrian Cortes * , Johanna Hadler * , Jenny P Pointon * , Philip C Robinson * , Tugce Karaderi * , Paul Leo * , Katie

Cremin * , Karena Pryce * , Jessica Harris * , Seunghun Lee * , Kyung Bin Joo * , Seung-Cheol Shim * , Michael Weisman * , Michael Ward * , Xiaodong Zhou * , Henri-Jean Garchon * , Gilles

Chiocchia * , Johannes Nossent * , Benedicte A Lie * , Øystein Førre * , Jaakko Tuomilehto * , Kari Laiho * , Lei Jiang * , Yu Liu * , Xin Wu * , Linda A Bradbury * , Dirk Elewaut * , Ruben

Burgos-Vargas * , Simon Stebbings * , Louise Appleton * , Claire Farrah * , Jonathan Lau * , Tony J Kenna * , Nigil Haroon * , Manuel A Ferreira * , Jian Yang * , Juan Mulero * , Jose Luis

Fernandez-Sueiro * , Miguel A Gonzalez-Gay * , Carlos Lopez-Larrea * , Panos Deloukas * , Peter Donnelly * , Australo-Anglo-American Spondyloarthritis Consortium (TASC) * , Groupe Française

d'Etude Génétique des Spondylarthrites (GFEGS) * , Nord-Trøndelag Health Study (HUNT) * , Spondyloarthritis Research Consortium of Canada (SPARCC) * , Wellcome Trust Case Control

Consortium 2 (WTCCC2) * , Paul Bowness * , Karl Gafney * , Hill Gaston * , Dafna D Gladman * , Proton Rahman * , Walter P Maksymowych * , Huji Xu * , J Bart A Crusius * , Irene E van der

Horst-Bruinsma * , Chung-Tei Chou * , Raphael Valle-Oñate * , Consuelo Romero-Sánchez * , Inger Myrnes Hansen * , Fernando M Pimentel-Santos * , Robert D Inman * , Vibeke Videm * , Javier

Martin * , Maxime Breban * , John D Reveille * , David M Evans * , Tae-Hwan Kim * , Bryan Paul Wordsworth *  & Matthew A Brown CONTRIBUTIONS J. Hadler, K.C., K.P. and J. Harris performed

genotyping. A.C., P.C.R., T.K., P.L., J.Y., M.A.B. and D.M.E. performed statistical analyses. J.P.P., S.L., K.B.J., S.-C.S., M. Weisman, M. Ward, X.Z., H.-J.G., G.C., J.N., B.A.L., Ø.F.,

J.T., K.L., L.J., Y.L., X.W., L.A.B., D.E., R.B.-V., S.S., L.A., C.F., J.L., N.H., J. Mulero, J.L.F.-S., M.A.G.-G., C.L.-L., P. Deloukas, P. Donnelly, P.B., K.G., H.G., D.D.G., P.R., W.P.M.,

H.X., J.B.A.C., I.E.v.d.H.-B., C.-T.C., R.V.-O., C.R.-S., I.M.H., F.M.P.-S., R.D.I., V.V., J. Martin, M.B., J.D.R. and T.-H.K. all contributed to subject recruitment and study design. A.C.,

M.A.B., D.M.E. and B.P.W. wrote the manuscript, and all authors contributed to manuscript drafting and reviewed the final manuscript. T.J.K. performed cell count and IL-6R studies in

ankylosing spondylitis cases and controls. M.A.F. performed GWAS of cell counts in controls. CORRESPONDING AUTHOR Correspondence to Matthew A Brown. ETHICS DECLARATIONS COMPETING INTERESTS

The author declare no competing financial interests. ADDITIONAL INFORMATION Details appear in the Supplementary Note. Details appear in the Supplementary Note. Details appear in the

Supplementary Note. Details appear in the Supplementary Note. Details appear in the Supplementary Note. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Tables 1–11,

Supplementary Figures 1–12, Supplementary Note (PDF 13979 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE International Genetics of Ankylosing

Spondylitis Consortium (IGAS). Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. _Nat Genet_ 45, 730–738 (2013).

https://doi.org/10.1038/ng.2667 Download citation * Received: 10 October 2012 * Accepted: 15 May 2013 * Published: 09 June 2013 * Issue Date: July 2013 * DOI: https://doi.org/10.1038/ng.2667

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