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

T. Niu, N. Liu, X. Yu, M. Zhao, H.J. Choi, P.J. Leo, M.A. Brown, L. Zhang, Y.F. Pei, H. Shen, H. He, X. Fu, S. Lu, X.D. Chen, L.J. Tan, T.L. Yang, Y. Guo, N.H. Cho, J. Shen, Y.F. Guo & 13 others G.C. Nicholson, Richard Prince, J.A. Eisman, G. Jones, P.N. Sambrook, Q. Tian, X.Z. Zhu, C.J. Papasian, E.L. Duncan, A.G. Uitterlinden, C.S. Shin, S. Xiang, H.W. Deng

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    © 2015 American Society for Bone and Mineral Research. 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.
    Original languageEnglish
    Pages (from-to)358-368
    Number of pages11
    JournalJournal of Bone and Mineral Research
    Volume31
    Issue number2
    Early online date11 Sep 2015
    DOIs
    Publication statusPublished - 11 Feb 2016

    Fingerprint

    Genome-Wide Association Study
    Bone Density
    Meta-Analysis
    Phosphorylation
    Single Nucleotide Polymorphism
    Femur Neck
    Computer Simulation
    Proteins
    Pelvic Bones
    Genome
    Phenotype
    Osteoporosis
    Spine

    Cite this

    Niu, T. ; Liu, N. ; Yu, X. ; Zhao, M. ; Choi, H.J. ; Leo, P.J. ; Brown, M.A. ; Zhang, L. ; Pei, Y.F. ; Shen, H. ; He, H. ; Fu, X. ; Lu, S. ; Chen, X.D. ; Tan, L.J. ; Yang, T.L. ; Guo, Y. ; Cho, N.H. ; Shen, J. ; Guo, Y.F. ; Nicholson, G.C. ; Prince, Richard ; Eisman, J.A. ; Jones, G. ; Sambrook, P.N. ; Tian, Q. ; Zhu, X.Z. ; Papasian, C.J. ; Duncan, E.L. ; Uitterlinden, A.G. ; Shin, C.S. ; Xiang, S. ; 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. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 2. pp. 358-368.
    @article{93fe16f10a2a49f3a60b7cd5f0aa126d,
    title = "Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies",
    abstract = "{\circledC} 2015 American Society for Bone and Mineral Research. 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.",
    author = "T. Niu and N. Liu and X. Yu and M. Zhao and H.J. Choi and P.J. Leo and M.A. Brown and L. Zhang and Y.F. Pei and H. Shen and H. He and X. Fu and S. Lu and X.D. Chen and L.J. Tan and T.L. Yang and Y. Guo and N.H. Cho and J. Shen and Y.F. Guo and G.C. Nicholson and Richard Prince and J.A. Eisman and G. Jones and P.N. Sambrook and Q. Tian and X.Z. Zhu and C.J. Papasian and E.L. Duncan and A.G. Uitterlinden and C.S. Shin and S. Xiang and H.W. Deng",
    year = "2016",
    month = "2",
    day = "11",
    doi = "10.1002/jbmr.2687",
    language = "English",
    volume = "31",
    pages = "358--368",
    journal = "Journal of Bone & Mineral Research",
    issn = "0884-0431",
    publisher = "John Wiley & Sons",
    number = "2",

    }

    Niu, T, Liu, N, Yu, X, Zhao, M, Choi, HJ, Leo, PJ, Brown, MA, Zhang, L, Pei, YF, Shen, H, He, H, Fu, X, Lu, S, Chen, XD, Tan, LJ, Yang, TL, Guo, Y, Cho, NH, Shen, J, Guo, YF, Nicholson, GC, Prince, R, Eisman, JA, Jones, G, Sambrook, PN, Tian, Q, Zhu, XZ, Papasian, CJ, Duncan, EL, Uitterlinden, AG, Shin, CS, Xiang, S & Deng, HW 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, vol. 31, no. 2, pp. 358-368. https://doi.org/10.1002/jbmr.2687

    Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies. / Niu, T.; Liu, N.; Yu, X.; Zhao, M.; Choi, H.J.; Leo, P.J.; Brown, M.A.; Zhang, L.; Pei, Y.F.; Shen, H.; He, H.; Fu, X.; Lu, S.; Chen, X.D.; Tan, L.J.; Yang, T.L.; Guo, Y.; Cho, N.H.; Shen, J.; Guo, Y.F.; Nicholson, G.C.; Prince, Richard; Eisman, J.A.; Jones, G.; Sambrook, P.N.; Tian, Q.; Zhu, X.Z.; Papasian, C.J.; Duncan, E.L.; Uitterlinden, A.G.; Shin, C.S.; Xiang, S.; Deng, H.W.

    In: Journal of Bone and Mineral Research, Vol. 31, No. 2, 11.02.2016, p. 358-368.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies

    AU - Niu, T.

    AU - Liu, N.

    AU - Yu, X.

    AU - Zhao, M.

    AU - Choi, H.J.

    AU - Leo, P.J.

    AU - Brown, M.A.

    AU - Zhang, L.

    AU - Pei, Y.F.

    AU - Shen, H.

    AU - He, H.

    AU - Fu, X.

    AU - Lu, S.

    AU - Chen, X.D.

    AU - Tan, L.J.

    AU - Yang, T.L.

    AU - Guo, Y.

    AU - Cho, N.H.

    AU - Shen, J.

    AU - Guo, Y.F.

    AU - Nicholson, G.C.

    AU - Prince, Richard

    AU - Eisman, J.A.

    AU - Jones, G.

    AU - Sambrook, P.N.

    AU - Tian, Q.

    AU - Zhu, X.Z.

    AU - Papasian, C.J.

    AU - Duncan, E.L.

    AU - Uitterlinden, A.G.

    AU - Shin, C.S.

    AU - Xiang, S.

    AU - Deng, H.W.

    PY - 2016/2/11

    Y1 - 2016/2/11

    N2 - © 2015 American Society for Bone and Mineral Research. 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.

    AB - © 2015 American Society for Bone and Mineral Research. 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.

    U2 - 10.1002/jbmr.2687

    DO - 10.1002/jbmr.2687

    M3 - Article

    VL - 31

    SP - 358

    EP - 368

    JO - Journal of Bone & Mineral Research

    JF - Journal of Bone & Mineral Research

    SN - 0884-0431

    IS - 2

    ER -