Hip shape shows a causal effect on hip fracture but not hip osteoarthritis: findings from a GWAS meta-analysis and causal analyses

ObjectivesHip 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. MethodsStatistical 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. ResultsAnalysis of the first 10 HSMs identified 290 independent association signals (P<5x10-8). Hip shape SNPs were also associated (P<1.7x10-4) 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=1.79x10-4 and OR 0.74 [0.65-0.84], P=7.60x10-6 respectively) ConclusionsWe 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. Key messagesO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSHip 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 ADDSThis 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 POLICYThis 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.