Faber Benjamin G, Frysz Monika, Zheng Jaiyi, Lin Huandong, Flynn Kaitlyn A, Ebsim Raja, Saunders Fiona R, Beynon Rhona, Gregory Jennifer S, Aspden Richard M, Harvey Nicholas C, Lindner Claudia, Cootes Timothy, Evans David M, Davey Smith George, Gao Xin, Wang Sijia, Kemp John P, Tobias Jonathan H
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.
Hum Mol Genet. 2025 Feb 1;34(3):207-217. doi: 10.1093/hmg/ddae169.
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.
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.
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).
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.
髋关节形状被认为是髋骨关节炎和骨折的一个重要因果风险因素。我们旨在确定髋关节形状的遗传决定因素，并利用这些因素评估与髋骨关节炎的因果关系。
采用统计髋关节形状建模方法，从英国生物银行和上海长风队列的双能X线吸收法（DXA）图像中得出10种髋关节形状模式（HSMs）（样本总量=43485）。对每种HSM进行全基因组关联研究荟萃分析。使用两样本孟德尔随机化（MR）方法，以髋部骨折作为阳性对照，估计HSM与髋骨关节炎之间的因果效应。
对前10种HSM的分析确定了203个独立关联信号（P<5×10⁻⁹）。髋关节形状单核苷酸多态性（SNPs）也与髋骨关节炎（n=26）和髋部骨折（n=4）相关（P<2.5×10⁻⁴）。精细定位表明，SMAD3和PLEC是可能参与髋关节形状和髋骨关节炎发展的候选基因。MR分析表明，任何HSM与髋骨关节炎之间均无因果效应，然而，有证据表明HSM2（颈干角更钝）和HSM4（股骨颈更宽）对髋部骨折有因果效应（逆方差加权法分别为1.27[95%CI 1.12 - 1.44]，P = 1.79×10⁻⁴和逆方差加权法0.74[0.65 - 0.84]，P = 7.60×10⁻⁶）。
我们报告了最大规模的髋关节形状全基因组关联研究荟萃分析，确定了数百个新位点，其中一些也与髋骨关节炎和髋部骨折相关。MR分析表明，髋关节形状可能不会导致髋骨关节炎，但与髋部骨折有关。因此，针对老年人髋关节形状进行干预以预防髋骨关节炎可能是无效的。
