The genetic architecture of hip shape and its role in the development of hip osteoarthritis and fracture.

Jonathan H Tobias, Timothy Cootes, Claudia Lindner, Raja Ebsim, Kaitlyn A Flynn, Jaiyi Zheng, Benjamin G Faber, Nicholas C Harvey, Sijia Wang, David M Evans, Richard M Aspden, George Davey Smith, Fiona R Saunders, Xin Gao, Monika Frysz, John P Kemp, Huandong Lin, Rhona Beynon, Jennifer S Gregory

Journal: Human molecular genetics 2025;34(3):207-217

PMID: 39574169

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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 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 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.

Address: Musculoskeletal Research Unit, Learning and Research Building, University of Bristol, Southmead Hospital, Bristol BS10 5NB, United Kingdom.; Medical Research Council Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2BN, United Kingdom.; CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 111 Yixueyuan Road, Xuhui District, Shanghai 200031, China.; Fudan Institute for Metabolic Diseases, Fudan University, Shanghai 200032, China.; Mater Research Institute, The University of Queensland, 37 Kent Street, Woolloongabba, Brisbane QLD 4102, Australia.; Division of Informatics, Imaging and Data Sciences, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.; Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Kings College, Aberdeen AB24 3FX, United Kingdom.; Musculoskeletal Research Unit, Learning and Research Building, University of Bristol, Southmead Hospital, Bristol BS10 5NB, United Kingdom.; Medical Research Council Lifecourse Epidemiology Centre, University of Southampton,Tremona Road, Southampton SO16 6YD, United Kingdom.; NIHR Southampton Biomedical Research Centre, University of Southampton, Tremona Road, Southampton SO16 6YD, United Kingdom.; University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom.; Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, Brisbane St Lucia QLD 4067, Australia.; The University of Queensland Diamantina Institute, The University of Queensland, Brisbane St Lucia, QLD 4072, Australia.; Medical Research Council Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2BN, United Kingdom.; Medical Research Council Integrative Epidemiology Unit, Oakfield House, University of Bristol, Bristol BS8 2BN, United Kingdom.; Mater Research Institute, The University of Queensland, 37 Kent Street, Woolloongabba, Brisbane QLD 4102, Australia.; Frazer Institute, The University of Queensland, 37 Kent Street, Woolloongabba, Brisbane QLD 4102, Australia.

DOI: 10.1093/hmg/ddae169