Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies

Niu, Tianhua, Liu, Ning, Yu, Xun, Zhao, Ming, Choi, Hyung Jin, Leo, Paul J., Brown, Matthew A., Zhang, Lei, Pei, Yu-Fang, Shen, Hui, He, Hao, Fu, Xiaoying, Lu, Shan, Chen, Xiang-Ding, Tan, Li-Jun, Yang, Tie-Lin, Guo, Yan, Cho, Nam H., Shen, Jie, Guo, Yan-Fang, Nicholson, Geoffrey C, Prince, Richard L., Eisman, John A., Jones, Graeme, Sambrook, Philip N., Tian, Qing, Zhu, Xue-Zhen, Papasian, Christopher J., Duncan, Emma L., Uitterlinden, André G., Shin, Chan Soo, Xiang, Shuanglin, & Deng, Hong-Wen (2016) Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies. Journal of Bone and Mineral Research, 31(2), pp. 358-368.

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Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10–6 (0.05/9593) and 1.00 × 10–4, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10–4) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10–3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10–10, p = 5.26 × 10–10, and p = 3.01 × 10–10, respectively) and HIP-BMD (p = 3.26 × 10–6, p = 1.97 × 10–6, and p = 1.63 × 10–12, respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants. © 2015 American Society for Bone and Mineral Research.

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ID Code: 93900
Item Type: Journal Article
Refereed: Yes
DOI: 10.1002/jbmr.2687
ISSN: 0884-0431
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > GENETICS (060400)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2015 American Society for Bone and Mineral Research
Deposited On: 18 Mar 2016 00:54
Last Modified: 23 Mar 2016 01:37

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