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Clinical and epidemiological research
Extended report
Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis
  1. Kalliope Panoutsopoulou1,
  2. Shankar Thiagarajah2,
  3. Eleni Zengini2,3,
  4. Aaron G Day-Williams1,4,
  5. Yolande FM Ramos5,
  6. Jennifer MTA Meessen5,6,
  7. Kasper Huetink6,
  8. Rob GHH Nelissen6,
  9. Lorraine Southam1,7,
  10. N William Rayner1,7,8,
  11. arcOGEN Consortium,
  12. Michael Doherty9,
  13. Ingrid Meulenbelt5,
  14. Eleftheria Zeggini1,
  15. J Mark Wilkinson2
    1. 1 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
    2. 2 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
    3. 3 5th Psychiatric Department, Dromokaiteio Psychiatric Hospital of Athens, Athens, Greece
    4. 4 Department of Genomics and Computational Biology, Biogen Idec, Cambridge, Massachusetts, USA
    5. 5 Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands
    6. 6 Department of Orthopaedics, LUMC, Leiden, The Netherlands
    7. 7 Wellcome Trust Centre for Human Genetics, Oxford, UK
    8. 8 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
    9. 9 Academic Rheumatology, University of Nottingham, Nottingham, UK
    1. Correspondence to Professor J Mark Wilkinson, Metabolic Bone Unit, Sorby Wing Northern General Hospital, Sheffield S5 7AU, UK; j.m.wilkinson{at}sheffield.ac.uk

    Abstract

    Objective Osteoarthritis (OA) has a strong genetic component but the success of previous genome-wide association studies (GWAS) has been restricted due to insufficient sample sizes and phenotype heterogeneity. Our aim was to examine the effect of clinically relevant endophenotyping according to site of maximal joint space narrowing (maxJSN) and bone remodelling response on GWAS signal detection in hip OA.

    Methods A stratified GWAS meta-analysis was conducted in 2118 radiographically defined hip OA cases and 6500 population-based controls. Signals were followed up by analysing differential expression of proximal genes for bone remodelling endophenotypes in 33 pairs of macroscopically intact and OA-affected cartilage.

    Results We report suggestive evidence (p<5×10−6) of association at 6 variants with OA endophenotypes that would have been missed by using presence of hip OA as the disease end point. For example, in the analysis of hip OA cases with superior maxJSN versus cases with non-superior maxJSN we detected association with a variant in the LRCH1 gene (rs754106, p=1.49×10−7, OR (95% CIs) 0.70 (0.61 to 0.80)). In the comparison of hypertrophic with non-hypertrophic OA the most significant variant was located between STT3B and GADL1 (rs6766414, p=3.13×10−6, OR (95% CIs) 1.45 (1.24 to 1.69)). Both of these associations were fully attenuated in non-stratified analyses of all hip OA cases versus population controls (p>0.05). STT3B was significantly upregulated in OA-affected versus intact cartilage, particularly in the analysis of hypertrophic and normotrophic compared with atrophic bone remodelling pattern (p=4.2×10−4).

    Conclusions Our findings demonstrate that stratification of OA cases into more homogeneous endophenotypes can identify genes of potential functional importance otherwise obscured by disease heterogeneity.

    • Osteoarthritis
    • Chondrocytes
    • Gene Polymorphism

    This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

    https://doi.org/10.1136/annrheumdis-2016-210373

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      Footnotes

      • Handling editor Tore K Kvien

      • KP, ST, IM, EZ and JMW contributed equally.

      • EZ and JMW are joint corresponding authors.

      • Collaborators Members of the arcOGEN Consortium: N Arden, F Birrell, A Carr, K Chapman, P Deloukas, M Doherty, J Loughlin, A McCaskie, WER Ollier, A Rai, SH Ralston, TD Spector, AM Valdes, GA Wallis, JM Wilkinson and E Zeggini.

      • Contributors Study concept and design: IM, JMW and EZeg. Acquisition of data: All. Analysis and interpretation of data: All. Statistical analysis: KP, ST, IM, JMW and EZeg. Drafting of manuscript: IM, KP, ST and JMW. Critical revision of manuscript for important intellectual content: All. IM, JMW and EZeg had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

      • Funding This work was supported by Arthritis Research UK (grant 19542, KP and EZ; grant 20308, KP), the Wellcome Trust (grant 098051, KP and EZ), the Joint Action Trust (grant GA1125, British Orthopaedic Association, ST and JMW) and the National Institute for Health Research funded Sheffield Bone Biomedical Research Unit (ST and JMW). This study used genotype data from arcOGEN (http://www.arcogen.org.uk/) funded by a special purpose grant from Arthritis Research UK (grant 18030). This study makes use of data generated by the Wellcome Trust Case-Control Consortium (the 1958 British Birth Cohort collection and the UK Blood Services Collection). A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk and funding for the project was provided by the Wellcome Trust under awards 076113, 085475 and 090355. The Leiden University Medical Center supports the RAAK Study, while research leading to these results has received funding from the Dutch Arthritis Association (DAA 2010_017) and the IDEAL project (European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679).

      • Competing interests None.

      • Ethics approval National Research Ethics Service.

      • Provenance and peer review Not commissioned; externally peer reviewed.