title: Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies.
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.
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Xun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.|Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Pei
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Fu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Tan
authors.affiliation: School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
authors.affiliation: School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Korea.
authors.forename: Nam H
authors.initials: NH
authors.lastname: Cho
authors.affiliation: Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China.
authors.forename: Yan-Fang
authors.initials: YF
authors.lastname: Guo
authors.affiliation: School of Medicine, The University of Queensland, Toowoomba, Australia.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Nicholson
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.|Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Prince
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: Jones
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sambrook
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.
authors.forename: Xue-Zhen
authors.initials: XZ
authors.lastname: Zhu
authors.affiliation: Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.|Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Chan Soo
authors.initials: CS
authors.lastname: Shin
authors.affiliation: College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.|College of Life Science, Hunan Normal University, Changsha, P.R. China.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005272:Femur Neck / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008159:Lumbar Vertebrae / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C417262:WNT16 protein, human; D051153:Wnt Proteins
keywords: HUMAN ASSOCIATION STUDIES; META-ANALYSIS; OSTEOPOROSIS; SINGLE-NUCLEOTIDE POLYMORPHISM; WNT/BETA-CATENIN/LRPS