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Basic and translational research
Concise report
A novel variant in GLIS3 is associated with osteoarthritis
  1. Elisabetta Casalone1,2,
  2. Ioanna Tachmazidou3,
  3. Eleni Zengini4,5,
  4. Konstantinos Hatzikotoulas3,
  5. Sophie Hackinger3,
  6. Daniel Suveges3,
  7. Julia Steinberg3,
  8. Nigel William Rayner3,6,7,
  9. arcOGEN Consortium,
  10. Jeremy Mark Wilkinson4,
  11. Kalliope Panoutsopoulou3,
  12. Eleftheria Zeggini3
    1. 1 Department of Medical Sciences, University of Turin, Turin, Italy
    2. 2 Italian Institute for Genomic Medicine, IIGM, Turin, Italy
    3. 3 Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
    4. 4 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
    5. 5 5th Psychiatric Department, Dromokaiteio Psychiatric Hospital of Athens, Athens, Greece
    6. 6 Wellcome Trust Centre for Human Genetics, Oxford, UK
    7. 7 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
    1. Correspondence to Dr Kalliope Panoutsopoulou, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1HH, UK; kp6{at}sanger.ac.uk

    Abstract

    Objectives Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.

    Methods We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.

    Results We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.

    Conclusions We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.

    • osteoarthritis
    • genome-wide association study
    • functional genomics
    • single nucleotide 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-2017-211848

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      Footnotes

      • KP and E Zeggini contributed equally.

      • Handling editor Tore K Kvien

      • Contributors Study concept and design: KP and EZeggini. Data analysis and interpretation: all authors. Manuscript preparation: KP and EC. Critical revision of manuscript for important intellectual content: all authors.

      • Funding This work has been funded by a career development fellowship awarded to KP (grant 20308) and by the Wellcome Trust (WT098051). arcOGEN (http://www.arcogen.org.uk/) was funded by a special purpose grant from Arthritis Research UK (grant 18030). The UK Household Longitudinal Study (UKHLS, also known as Understanding Society study) was funded by grants from the Economic & Social Research Council (ES/H029745/1) and the Wellcome Trust (WT098051). UKHLS is led by the Institute for Social and Economic Research at the University of Essex. 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/. This research has been conducted using the UK Biobank Resource.

      • Competing interests None declared.

      • Ethics approval Oxfordshire REC, 3 January 2008, REC ref. no. 07/H0606/150.

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

      • Data sharing statement Genotype data of the arcOGEN cases and the UKHLS controls have been deposited at the European Genome-phenome Archive under study accession numbers EGAS00001001017 and EGAS00001001232, respectively.

      • Collaborators Members of the arcOGEN Consortium: John Loughlin, Nigel Arden, Fraser Birrell, Andrew Carr, Panos Deloukas, Michael Doherty, Andrew W McCaskie, William E R Ollier, Ashok Rai, Stuart H Ralston, Tim D Spector, Ana M Valdes, Gillian A Wallis, Jeremy Mark Wilkinson and Eleftheria Zeggini.