Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.
Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.
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DOI：
10.1002/jbmr.3605
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Tobias JH
中科院分区：
文献类型：
--
作者：
Baird DA;Evans DS;Kamanu FK;Gregory JS;Saunders FR;Giuraniuc CV;Barr RJ;Aspden RM;Jenkins D;Kiel DP;Orwoll ES;Cummings SR;Lane NE;Mullin BH;Williams FM;Richards JB;Wilson SG;Spector TD;Faber BG;Lawlor DA;Grundberg E;Ohlsson C;Pettersson-Kymmer U;Capellini TD;Richard D;Beck TJ;Evans DM;Paternoster L;Karasik D;Tobias JH
我们的目的是报告第一个全基因组关联研究（GWAS）Meta分析的双能X线吸收测定法（DXA）得出的髋关节形状，这被认为是与髋关节骨关节炎和髋关节骨折的风险。使用SHAPE软件通过统计形状建模，从Avon父母和儿童纵向研究（ALSPAC;成年女性）、TwinsUK（混合性别）、FOS骨质疏松研究（FOS;混合）、男性骨质疏松性骨折研究（MrOS）和骨质疏松性骨折研究（SOF;女性）（总N = 15，934）的髋关节DXA扫描中推导出10种髋关节形状模式（HSM）。协会调整了年龄，性别和血统。5个全基因组显著（p < 5 × 10−9，经10个独立结果调整）的单核苷酸多态性（SNP）与HSM 1相关，3个SNP与HSM 2相关。一个SNP，与与HSM 1相关的rs 2158915高度连锁不平衡，与HSM 5在全基因组意义上相关。在对以前的GWAS的查找中，确定的SNP中有三个与髋关节骨关节炎相关，一个与髋部骨折相关，五个与身高相关。在参与软骨内骨形成的基因的200 kb内有7个SNP，即SOX 9、PTHrP、RUNX 1、NKX 3 - 2、FGFR 4、DICER 1和HHIP。与DICER 1相邻的SNP也显示了GSC的成骨细胞顺式调节活性，其中突变先前已被报道导致髋关节发育不良。对于三个前导SNP，鉴定了高LD（r2> 0.5）中的SNP，其与开放染色质位点重叠，如通过在胚胎小鼠近端股骨上进行的ATAC-seq检测到的。总之，我们确定了8个与髋关节形状独立相关的SNP，其中大多数与身高相关和/或与软骨内骨形成基因密切相关，这与肢体生长过程对髋关节形状和病理后遗症的贡献一致。这些发现提出了一种可能性，即对髋关节形状的遗传研究可能有助于了解髋关节骨关节炎和髋关节骨折的潜在途径。版权所有© 2018作者.骨与矿物质研究杂志由Wiley Periodicals，Inc.出版。
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 × 10−9, 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 2 > 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.
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
7
作者：
Grundberg, Elin;Kwan, Tony;Pastinen, Tomi
通讯作者：
Pastinen, Tomi
影响因子：
30.8
作者：
Benko, Sabina;Fantes, Judy A.;Lyonnet, Stanislas
通讯作者：
Lyonnet, Stanislas
影响因子：
--
作者：
Baker-Lepain, Julie C;Lynch, John A;Parimi, Neeta;McCulloch, Charles E;Nevitt, Michael C;Corr, Maripat;Lane, Nancy E
通讯作者：
Lane, Nancy E