Genome-wide association study of DXA-derived hip morphology identifies associations with 4 loci in Chinese populations

Objective: To identify genetic factors associated with hip morphology in Chinese populations. Methods: An 85-point Statistical Shape Model (SSM) was applied to extract hip shape modes (HSMs). Diameter of the femoral head (DFH), femoral neck width (FNW) and hip axis length (HAL) were obtained from SSM points using Python scripts. Genome-wide association study (GWAS) was conducted in the Shanghai Changfeng (SC) cohort (N=5,310) for each phenotype of DXA-derived hip morphology. Replication of GWAS was conducted in the Core cohort (N=917). Results: GWAS identified a total of 331 SNPs in 14 loci that were associated with features of hip morphology in the SC cohort. 4 of 14 loci were replicated in the Core cohort: rs143383 (GDF5) associated with HAL (P = 9.4×10−10), rs11614913 (MIR196A2) associated with HSM9 (P = 2.8 ×10−10), rs35049516 (SUPT3H) associated with HSM4 (P = 4.3×10−10) and rs7761119 (UST) associated with HSM8 (P = 1.7×10−8). Of these, two loci were known to affect hip morphology, including rs143383 (GDF5) and rs35049516 (SUPT3H), whereas rs11614913 (MIR196A2) and rs7761119 (UST) were novel. There was also overlap with previous GWAS of HSM and other hip-based metrics. Conclusions: In the largest East Asian ancestry hip shape GWAS to date we identified and replicated four loci associated with different aspects of hip morphology (GDF5, MIR196A2, SUPT3H, UST). Strong SNP-to-gene evidence was found. All four loci have previously been implicated in musculoskeletal development, however this is the first report that rs11614913 (MIR196A2) and rs7761119 (UST) are associated with hip morphology. Despite the small sample size, this study paves the way for trans-ancestry meta-analyses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB38020400), the CAS Project for Young Scientists in Basic Research (Grant No. YSBR-077), Shanghai Science and Technology Commission Excellent Academic Leaders Program (22XD1424700), Shanghai Municipal Science and Technology Major Project (Grant No.2017SHZDZX01), Wellcome Trust and the Royal Society (223267/Z/21/Z), Wellcome Trust collaborative award (209233), Wellcome Trust [Grant numbers: 209233, 223267/Z/21/Z] and a Medical Research Council (MRC) clinical research training fellowship (MR/ S021280/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Zhong Shan Hospital of Fudan University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors