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

Citation

Niu, T and Liu, N and Yu, X and Zhao, M and Choi, HJ and Leo, PJ and Brown, MA and Zhang, L and Pei, Y-F and Shen, H and He, H and Fu, X and Lu, S and Chen, X-D and Tan, L-J and Yang, T-L and Guo, Y and Cho, NH and Shen, J and Guo, Y-F and Nicholson, GC and Prince, RL and Eisman, JA and Jones, G and Sambrook, PN and Tian, Q and Zhu, X-Z and Papasian, CJ and Duncan, EL and Uitterlinden, AG and Shin, CS and Xiang, S and Deng, H-W, 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. ISSN 1523-4681 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 American Society for Bone and Mineral Research

DOI: doi:10.1002/jbmr.2687

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.

Item Details

Item Type:Refereed Article
Keywords:osteoporosis, human association studies, single-nucleotide polymorphism, meta-analysis WNT/Beta-Catenin/LRPS
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Rheumatology and Arthritis
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Skeletal System and Disorders (incl. Arthritis)
Author:Jones, G (Professor Graeme Jones)
ID Code:103046
Year Published:2015
Web of Science® Times Cited:5
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-09-16
Last Modified:2017-11-03
Downloads:0

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