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Polygenic risk scores have high diagnostic capacity in ankylosing spondylitis.

Research output: Contribution to journalArticlepeer-review

Zhixiu Li, Xin Wu, Paul J. Leo, Erika De Guzman, Nurullah Akkoc, Maxime Breban, Gary J. MacFarlane, Mahdi Mahmoudi, Helena Marzo-Ortega, Lisa K. Anderson, Lawrie Wheeler, Chung Tei Chou, Andrew A. Harrison, Simon Stebbings, Gareth T. Jones, So Young Bang, Geng Wang, Ahmadreza Jamshidi, Elham Farhadi, Jing Song & 21 more Li Lin, Mengmeng Li, James Cheng Chung Wei, Nicholas G. Martin, Margaret J. Wright, Min Jae Lee, Yuqin Wang, Jian Zhan, Jin San Zhang, Xiaobing Wang, Zi Bing Jin, Michael H. Weisman, Lianne S. Gensler, Michael M. Ward, Mohammad Hossein Rahbar, Laura Diekman, Tae Hwan Kim, John D. Reveille, Bryan Paul Wordsworth, Huji Xu, Matthew A. Brown

Original languageEnglish
Article numberannrheumdis-2020- 219446
Pages (from-to)1168-1174
Number of pages7
JournalAnnals of the rheumatic diseases
Issue number9
Early online date21 Apr 2021
Accepted/In press2021
E-pub ahead of print21 Apr 2021
Published1 Sep 2021

Bibliographical note

Funding Information: Twitter Nurullah Akkoc @nurullahakkoc, Gary J Macfarlane @UAberdeenEpi and Gareth T Jones @hteraG_senoJ Acknowledgements We would like to thank all participating subjects with ankylosing spondylitis and healthy individuals who provided the DNA and clinical information necessary for this study. The TASC study was funded by the 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 Health Science Center at Houston CTSA grant UL1RR02418, Cedars-Sinai GCRC grant MO1-RR00425, Intramural Research Program, NIAMS/NIH and Rebecca Cooper Foundation (Australia). Funding Information: Funding This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (grant number 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). XH is supported by the National Natural Science Foundation of China (Grant No. 31821003), National Key Research and Development Project (Grant No. 2018AAA0100302), Shanghai Municipal Key Clinical Specialty (shslczdzk02602), and Shanghai Science and Technology Development Funds (2020-SH-XY-2). ZBJ was funded by a grant from the Zhejiang Provincial Natural Science Foundation of China (LD18H120001LD). The New Zealand data were derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. We acknowledge the Understanding Society: The UK Household Longitudinal Study. This is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https: www. HMO is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. French sample collection was performed by the Groupe Française d’Etude Génétique des Spondylarthrites, coordinated by Professor Maxime Breban and funded by the Agence Nationale de Recherche GEMISA grant reference ANR-10-MIDI-0002. We acknowledge and thank the TCRI AS Group for their support in recruiting patients for the study (see below). The authors acknowledge the sharing of data and samples by the BSRBR-AS Register in Aberdeen. Chief Investigator, Professor Gary Macfarlane and Dr Gareth Jones, Deputy Chief Investigator created the BSRBR-AS study which was commissioned by the British Society for Rheumatology, funded in part by Abbvie, Pfizer and UCB. We are grateful to every patient, past and present staff of the BSRBR-AS register team and to all clinical staff who recruited patients, followed them up and entered data—details here: https:// The QIMR control samples were from parents of adolescent twins collected in the context of the Brisbane Longitudinal Twin Study 1992–2016, support by grants from NHMRC (NGM) and ARC (MJW). We thank Anjali Henders, Lisa Bowdler, Tabatha Goncales for biobank collection and Kerrie McAloney and Scott Gordon for curating samples for this study. MAB is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship (1024879), 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 Rebecca Cooper Medical Research Foundation. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for patient recruitment was provided by the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and an unrestricted educational grant from Abbott Laboratories. This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


We sought to test the hypothesis that polygenic risk scores (PRS) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.
PRS were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15,083 AS cases and 20,902 controls. The discriminatory value of PRS in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac magnetic resonance imaging (MRI).
In people of European ethnicity, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885), or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients, and negative predictive values for 67.5% of patients. For PRS, the maximum positive predictive value was 78.2% and negative predictive value 100%, whereas for HLA-B27 these values were 51.9% and 97.9% respectively.
PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI, or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

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