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

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.