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, Andre G., Shin, Chan Soo, Xiang, Shuanglin and 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: 358-368. doi:10.1002/jbmr.2687


Author 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, Andre G.
Shin, Chan Soo
Xiang, Shuanglin
Deng, Hong-Wen
Title Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies
Formatted title
Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 1523-4681
0884-0431
Publication date 2016-02
Sub-type Article (original research)
DOI 10.1002/jbmr.2687
Open Access Status Not Open Access
Volume 31
Issue 2
Start page 358
End page 368
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley and Sons
Collection year 2017
Language eng
Formatted abstract
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.
Keyword Human association studies
Meta-analysis
Osteoporosis
Single-nucleotide polymorphism
Wnt/beta-catenin/LRPS
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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