Abstract
Objective Minimum joint space width (mJSW) from 2-dimensional images 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 use them to (ii) examine causal effects of mJSW on hip osteoarthritis (HOA) risk.
Methods GWAS meta-analysis of hip mJSW derived from plain X-rays (four cohorts) or DXA (one cohort) 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.
Results 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci (35 novel), were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (βIVW -0.01 [95% CI -0.19, 0.17]). 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.
Conclusions GWAS and MR analyses suggested one group of mJSW loci reduces 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 mJSW and HOA risk via a growth-related mechanism.
Competing Interest Statement
TC & CL have a patent Image processing apparatus and method for fitting a deformable shape model to an image using random forest regression voting. This is licensed with royalties to Optasia Medical. NH reports consultancy fees and honoraria from UCB, Amgen, Kyowa Kirin, Thornton Ross, Consilient.
Funding Statement
MF, RE, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). BGF is supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). ML is supported by a University of Queensland Research Training Scholarship from The University of Queensland (UQ). ML thanks the Commonwealth Scientific and Industrial Research Organisation for the support through a Postgraduate Top-Up Scholarship. CL was funded by the MRC (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant numbers 080280/Z/06/Z, 20378/Z/16/Z, 223267/Z/21/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. NCH acknowledges support from the MRC (MC_PC_21003; MC_PC_21001) and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton. BGF, MF, AEH, GDS, JHT work in the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the MRC (MC_UU_00011/1). JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938). DSE acknowledges funding from NIH/NIA U24AG051129. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institute of Health funding from the following institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
UKB study (application number 17295) is overseen by the Ethics Advisory Committee and received approval from the National Information Governance Board for Health and Social Care and Northwest Multi-Centre Research Ethics Committee (11/NW/0382), all participants provided informed consent for this study. The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport (Population Screening Act WBO, license number 1071272-159521-PG). The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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Data Availability
The UK Biobank mJSW data from this study will be available in a forthcoming data release. Users must be registered with UK Biobank to access their resources (https://bbams.ndph.ox.ac.uk/ams/).