The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analysesResearch in context
Benjamin G. Faber,
Monika Frysz,
Cindy G. Boer,
Daniel S. Evans,
Raja Ebsim,
Kaitlyn A. Flynn,
Mischa Lundberg,
Lorraine Southam,
April Hartley,
Fiona R. Saunders,
Claudia Lindner,
Jennifer S. Gregory,
Richard M. Aspden,
Nancy E. Lane,
Nicholas C. Harvey,
David M. Evans,
Eleftheria Zeggini,
George Davey Smith,
Timothy Cootes,
Joyce Van Meurs,
John P. Kemp,
Jonathan H. Tobias
Affiliations
Benjamin G. Faber
Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Corresponding author. NIHR Academic Clinical Lecturer in Rheumatology Musculoskeletal Research Unit, Learning and Research Building, Level One, Southmead Hospital, Bristol BS10 5NB, UK.
Monika Frysz
Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK
Cindy G. Boer
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands
Daniel S. Evans
California Pacific Medical Center Research Institute, San Francisco, USA
Raja Ebsim
Division of Informatics, Imaging and Data Sciences, The University of Manchester, UK
Kaitlyn A. Flynn
Mater Research Institute, The University of Queensland, Woolloongabba, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia
Mischa Lundberg
UQ Frazer Institute, The University of Queensland, Woolloongabba, Australia
Lorraine Southam
Institute of Translational Genomics, Helmholtz Zentrum München – German Research Centre for Environmental Health, Neuherberg, Germany
April Hartley
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK
Fiona R. Saunders
Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, UK
Claudia Lindner
Division of Informatics, Imaging and Data Sciences, The University of Manchester, UK
Jennifer S. Gregory
Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, UK
Richard M. Aspden
Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, UK
Nancy E. Lane
Center for Musculoskeletal Health, University of California Davis, Sacramento, USA
Nicholas C. Harvey
Medical Research Council Lifecourse Epidemiology Centre, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, UK
David M. Evans
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia; UQ Frazer Institute, The University of Queensland, Woolloongabba, Australia
Eleftheria Zeggini
Institute of Translational Genomics, Helmholtz Zentrum München – German Research Centre for Environmental Health, Neuherberg, Germany; Technical University of Munich and Klinikum Rechts der Isar, TUM School of Medicine, Germany
George Davey Smith
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK
Timothy Cootes
Division of Informatics, Imaging and Data Sciences, The University of Manchester, UK
Joyce Van Meurs
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands
John P. Kemp
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK; Mater Research Institute, The University of Queensland, Woolloongabba, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia
Jonathan H. Tobias
Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK
Summary: Background: Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. Methods: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. Findings: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82–1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. Interpretations: One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism. Funding: Primarily funded by the Medical Research Council and Wellcome Trust.
