Hip Shape Shows a Causal Effect on Hip Fracture but Not Hip Osteoarthritis: Findings from a GWAS Meta-Analysis and Causal Analyses

Objectives Hip shape is thought to be an important causal risk factor for hip osteoarthritis and fracture. We aimed to identify genetic determinants of hip shape and use these to assess causal relationships with hip osteoarthritis. Methods Statistical hip shape modelling was used to derive 10 hip shape modes (HSMs) from DXA images in UK Biobank and Shanghai Changfeng cohorts (ntotal=43,485). Genome-wide association study meta-analyses were conducted for each HSM. Two-sample Mendelian randomisation (MR) was used to estimate causal effects between HSM and hip osteoarthritis using hip fracture as a positive control. Results Analysis of the first 10 HSMs identified 290 independent association signals (P<5×10-8). Hip shape SNPs were also associated (P<1.7×10-4) with hip osteoarthritis (n=29) and hip fracture (n=4). Fine mapping implicated SMAD3 and PLEC as candidate genes that may be involved in the development of hip shape and hip osteoarthritis. MR analyses suggested there was no causal effect between any HSM and hip osteoarthritis, however there was evidence that HSM2 (higher neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (ORIVW 1.27 [95% CI 1.12-1.44], P=1.79×10-4 and OR 0.74 [0.65-0.84], P=7.60×10-6 respectively) Conclusions We report the largest hip shape GWAS meta-analysis that identifies hundreds of novel loci, some of which are also associated with hip osteoarthritis and hip fracture. MR analyses suggest hip shape may not cause hip osteoarthritis but is implicated in hip fractures. Consequently, interventions aimed at modifying hip shape in older adults to prevent hip osteoarthritis may prove ineffective. WHAT IS ALREADY KNOWN ON THIS TOPIC Hip shape in many forms has been linked with an increased risk of hip osteoarthritis and hip fracture. These observational associations have led to the inference of causality, prompting the development of surgical treatments aimed at modifying hip shape to potentially prevent hip osteoarthritis. Unfortunately, observational studies are susceptible to confounding and reverse causation. WHAT THIS STUDY ADDS This study provides a comprehensive catalogue of genetic associations related to variations in hip shape, in the form of 10 orthogonal hip shape modes. Substantial genetic overlap was observed between hip shape and both hip osteoarthritis and fracture. However, MR analyses suggested there was no causal effect between hip shape and hip osteoarthritis. Conversely, there was strong evidence that hip shape variation, including greater neck-shaft angle, is causal for hip fractures. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY This study suggests that, at a population level, moderate hip shape variation does not cause hip osteoarthritis, meaning previously seen observational associations are likely confounded or due to reverse causality. Therefore, targeting these variations of hip shape through surgery, especially in older populations, may prove ineffective in preventing hip osteoarthritis. ### Competing Interest Statement CL has a patent for an 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 Amgen, UCB, Kyowa Kirin, Theramex. ### Funding Statement BGF is supported by a NIHR Academic Clinical Lectureship and was previously supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/S021280/1). RE, MF, FS were supported, and this work is funded by a Wellcome Trust collaborative award (209233/Z/17/Z). MF conducted this work whilst working at the University of Bristol but is now employed by Boehringer Ingleheim UK and Ireland. CL is funded by 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 Medical Research Council (MRC) [MC\_PC\_21003; MC\_PC\_21001] and National Institute for Health and Care Research (NIHR) Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. JPK is funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938). SW is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB38020400) and Shanghai Municipal Science and Technology Major Project, Grant No.2017SHZDZX01. XG is supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01). ### 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: The National Information Governance Board for Health and Social Care and Northwest Multi-Centre Research Ethics Committee (11/NW/0382) and UK Biobank Ethics Advisory committee gave ethical approval for all work in this study undertaken with UK Biobank data (UK Biobank application number 17295). The Zhongshan Hospital ethics committee affiliated to Fudan University gave ethical approval for this work (B2008-119(3)). All participants provided informed consent for this study. 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The HSM GWAS meta-analysis summary statistics will be uploaded to the GWAS catalog (). The individual level data from this study concerning UKB participants is available via their data showcase. Users must be registered with UK Biobank to access their resources ().