Abstract
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 metaanalyses 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 203 independent association signals (P<5×10-9). Hip shape SNPs were also associated (P<2.5×10-4) with hip osteoarthritis (n=26) 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 (more obtuse neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (ORIVW method 1.27 [95% CI 1.12-1.44], P=1.79×10-4
and ORIVW 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 targeting hip shape in older adults to prevent hip osteoarthritis may prove ineffective.
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 metaanalyses 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 203 independent association signals (P<5×10-9). Hip shape SNPs were also associated (P<2.5×10-4) with hip osteoarthritis (n=26) 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 (more obtuse neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (ORIVW method 1.27 [95% CI 1.12-1.44], P=1.79×10-4
and ORIVW 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 targeting hip shape in older adults to prevent hip osteoarthritis may prove ineffective.
| Original language | English |
|---|---|
| Pages (from-to) | 207-217 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 34 |
| Issue number | 3 |
| Early online date | 22 Nov 2024 |
| DOIs | |
| Publication status | Published - 1 Feb 2025 |
Bibliographical note
The authors would like to thank the Musculoskeletal Research Unit patient and public involvement group at the University of Bristol for their input into planning our research. This work has been conducted using the UK Biobank resource (application number 17295). BGF is supported by an NIHR Academic Clinical Lectureship, an Academy of Medical Sciences Starter Grant (SGL030\1057) 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 creative commons attribution license (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).Data Availability Statement
The HSM GWAS meta-analysis summary statistics will be uploaded to the GWAS catalog (https://www.ebi.ac.uk/gwas/). 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 (https://bbams.ndph.ox.ac.uk/ams/).Supplementary data is available at HMG Journal online.
Keywords
- genome wide association study
- osteoarthritis
- hip shape
- hip fracture
- Mendelian randomisation