Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
J Bone Miner Res. 2019 Feb;34(2):241-251. doi: 10.1002/jbmr.3605. Epub 2018 Nov 26.
We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
我们旨在报告双能 X 射线吸收法（DXA）衍生的髋关节形状的全基因组关联研究（GWAS）元分析，该分析被认为与髋关节骨关节炎和髋部骨折的风险都有关。使用 SHAPE 软件通过统计形状建模从 Avon Longitudinal Study of Parents and Children（ALSPAC；成年女性）、TwinsUK（混合性别）、Framingham Osteoporosis Study（FOS；混合）、Osteoporotic Fractures in Men study（MrOS）和 Study of Osteoporotic Fractures（SOF；女性）的髋部 DXA 扫描中得出了 10 种髋关节形状模式（HSM）（总 N=15934）。关联在调整年龄、性别和祖先后进行。5 个单核苷酸多态性（SNP）与 HSM1 相关，且 3 个 SNP 与 HSM2 相关，达到全基因组显著性（p<5×10-8，调整 10 个独立结果）。与 HSM1 高度连锁的 rs2158915 相关的一个 SNP 与 HSM5 也达到了全基因组显著性。在对先前的 GWAS 进行的查找中，鉴定出的 3 个 SNP 与髋关节骨关节炎相关，1 个 SNP 与髋部骨折相关，5 个 SNP 与身高相关。7 个 SNP 位于参与软骨内骨形成的基因的 200kb 以内，即 SOX9、PTHrP、RUNX1、NKX3-2、FGFR4、DICER1 和 HHIP。与 DICER1 相邻的 SNP 也显示出 GSC 的成骨细胞顺式调控活性，先前有报道称该 SNP 突变会导致髋关节发育不良。对于 3 个主要 SNP，鉴定出与高度 LD（r>0.5）的 SNP 相关，这些 SNP 与通过在胚胎小鼠近侧股骨上进行的 ATAC-seq 检测到的开放染色质位点相交。总之，我们鉴定出 8 个 SNP 与髋关节形状独立相关，其中大多数与身高相关，或与软骨内骨形成基因相邻，这与参与肢体生长的过程对髋关节形状和病理后果的贡献一致。这些发现提示对髋关节形状的遗传研究可能有助于理解髋关节骨关节炎和髋部骨折相关的潜在途径。
