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J Bone Miner Res. 2016 Feb;31(2):358-68. doi: 10.1002/jbmr.2687. Epub 2015 Sep 11.

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies.

Author information

1
Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
2
College of Life Science, Hunan Normal University, Changsha, P.R. China.
3
Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
4
Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.
5
University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
6
Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, P.R. China.
7
School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
8
Department of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Korea.
9
Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China.
10
School of Medicine, The University of Queensland, Toowoomba, Australia.
11
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
12
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia.
13
Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
14
Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
15
Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
16
Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA.
17
Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
18
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
19
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
20
Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.

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.

KEYWORDS:

HUMAN ASSOCIATION STUDIES; META-ANALYSIS; OSTEOPOROSIS; SINGLE-NUCLEOTIDE POLYMORPHISM; WNT/BETA-CATENIN/LRPS

PMID:
26256109
PMCID:
PMC5362379
DOI:
10.1002/jbmr.2687
[Indexed for MEDLINE]
Free PMC Article

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