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 analyses

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

doi:10.1016/j.ebiom.2023.104759

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 analyses

EBioMedicine. 2023 Sep:95:104759. doi: 10.1016/j.ebiom.2023.104759. Epub 2023 Aug 22.

Authors

Benjamin G Faber¹, Monika Frysz², Cindy G Boer³, Daniel S Evans⁴, Raja Ebsim⁵, Kaitlyn A Flynn⁶, Mischa Lundberg⁷, Lorraine Southam⁸, April Hartley⁹, Fiona R Saunders¹⁰, Claudia Lindner⁵, Jennifer S Gregory¹⁰, Richard M Aspden¹⁰, Nancy E Lane¹¹, Nicholas C Harvey¹², David M Evans¹³, Eleftheria Zeggini¹⁴, George Davey Smith⁹, Timothy Cootes⁵, Joyce Van Meurs³, John P Kemp¹⁵, Jonathan H Tobias²

Affiliations

¹ Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK. Electronic address: ben.faber@bristol.ac.uk.
² Musculoskeletal Research Unit, University of Bristol, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK.
³ Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.
⁴ California Pacific Medical Center Research Institute, San Francisco, USA.
⁵ Division of Informatics, Imaging and Data Sciences, The University of Manchester, UK.
⁶ Mater Research Institute, The University of Queensland, Woolloongabba, Australia; Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.
⁷ UQ Frazer Institute, The University of Queensland, Woolloongabba, Australia.
⁸ Institute of Translational Genomics, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg, Germany.
⁹ Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK.
¹⁰ Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, UK.
¹¹ Center for Musculoskeletal Health, University of California Davis, Sacramento, USA.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ 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.

Abstract

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 (OR_IVW 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.

Keywords: Cartilage; Genome-wide association study; Mendelian randomisation; Osteoarthritis.

Publication types

Meta-Analysis

MeSH terms

Cluster Analysis
Genome-Wide Association Study*
Humans
Joints
Mendelian Randomization Analysis
Osteoarthritis, Hip* / diagnostic imaging
Osteoarthritis, Hip* / genetics

Abstract

Publication types

MeSH terms

Grants and funding