Polygenic risk scores have high diagnostic capacity in ankylosing spondylitis

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 15,585 AS cases and 20,452 controls. The discriminatory values of PRSs 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.

Original languageEnglish
Article numberannrheumdis-2020-219446
Pages (from-to)1168-1174
Number of pages7
JournalAnnals of the Rheumatic Diseases
Issue number9
Early online date20 Apr 2021
Publication statusPublished - 12 Aug 2021

Bibliographical note

We would like to thank all participating subjects with AS 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, 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). 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). JZB was funded by a grant from the Zhejiang Provincial Natural Science Foundation of China (LD18H120001LD). The New Zealand data was derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. HX was funded by the National Natural Science Foundation of China (Grant 81430031) and China Ministry of Science and Technology (973 Program of China 2014CB541800). 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.understandingsociety.ac.uk/. 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, Prof 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://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011. 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.


  • Ankylosing spondylitis
  • Polygenic risk score
  • HLA-B27
  • CRP
  • MRI
  • Immunology
  • General Biochemistry, Genetics and Molecular Biology
  • Immunology and Allergy
  • Rheumatology


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