Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

T. Niu; N. Liu; M. Zhao; G. Xie; L. Zhang; J. Li; Y.F. Pei; H. Shen; X. Fu; H. He; S. Lu; X.D. Chen; L.J. Tan; T.L. Yang; Y. Guo; P.J. Leo; E.L. Duncan; J. Shen; Y.F. Guo; G.C. Nicholson; Richard Prince; J.A. Eisman; G. Jones; P.N. Sambrook; X. Hu; P.M. Das; Q. Tian; X.Z. Zhu; C.J. Papasian; M.A. Brown; A.G. Uitterlinden; Y.P. Wang; S. Xiang; H.W. Deng

doi:10.1093/hmg/ddv144

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

T. Niu, N. Liu, M. Zhao, G. Xie, L. Zhang, J. Li, Y.F. Pei, H. Shen, X. Fu, H. He, S. Lu, X.D. Chen, L.J. Tan, T.L. Yang, Y. Guo, P.J. Leo, E.L. Duncan, J. Shen, Y.F. Guo, G.C. NicholsonRichard Prince, J.A. Eisman, G. Jones, P.N. Sambrook, X. Hu, P.M. Das, Q. Tian, X.Z. Zhu, C.J. Papasian, M.A. Brown, A.G. Uitterlinden, Y.P. Wang, S. Xiang, H.W. Deng

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Abstract

© The Author 2015. Published by Oxford University Press. All rights reserved. MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10^-6. By applying α=5×10^-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10^-6 and 1.58×10^-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10^-3) at α=0.10/11=9.09×10^-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10^-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10^-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.

Original language	English
Pages (from-to)	4710-4727
Journal	Human Molecular Genetics
Volume	24
Issue number	16
Early online date	4 May 2015
DOIs	https://doi.org/10.1093/hmg/ddv144
Publication status	Published - 16 Aug 2015

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Niu, T., Liu, N., Zhao, M., Xie, G., Zhang, L., Li, J., Pei, Y. F., Shen, H., Fu, X., He, H., Lu, S., Chen, X. D., Tan, L. J., Yang, T. L., Guo, Y., Leo, P. J., Duncan, E. L., Shen, J., Guo, Y. F., ... Deng, H. W. (2015). Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies. Human Molecular Genetics, 24(16), 4710-4727. https://doi.org/10.1093/hmg/ddv144

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title = "Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies",

abstract = "{\textcopyright} The Author 2015. Published by Oxford University Press. All rights reserved. MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.",

author = "T. Niu and N. Liu and M. Zhao and G. Xie and L. Zhang and J. Li and Y.F. Pei and H. Shen and X. Fu and H. He and S. Lu and X.D. Chen and L.J. Tan and T.L. Yang and Y. Guo and P.J. Leo and E.L. Duncan 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 X. Hu and P.M. Das and Q. Tian and X.Z. Zhu and C.J. Papasian and M.A. Brown and A.G. Uitterlinden and Y.P. Wang and S. Xiang and H.W. Deng",

year = "2015",

month = aug,

day = "16",

doi = "10.1093/hmg/ddv144",

language = "English",

volume = "24",

pages = "4710--4727",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

Niu, T, Liu, N, Zhao, M, Xie, G, Zhang, L, Li, J, Pei, YF, Shen, H, Fu, X, He, H, Lu, S, Chen, XD, Tan, LJ, Yang, TL, Guo, Y, Leo, PJ, Duncan, EL, Shen, J, Guo, YF, Nicholson, GC, Prince, R, Eisman, JA, Jones, G, Sambrook, PN, Hu, X, Das, PM, Tian, Q, Zhu, XZ, Papasian, CJ, Brown, MA, Uitterlinden, AG, Wang, YP, Xiang, S & Deng, HW 2015, 'Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies', Human Molecular Genetics, vol. 24, no. 16, pp. 4710-4727. https://doi.org/10.1093/hmg/ddv144

TY - JOUR

T1 - Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

AU - Niu, T.

AU - Liu, N.

AU - Zhao, M.

AU - Xie, G.

AU - Zhang, L.

AU - Li, J.

AU - Pei, Y.F.

AU - Shen, H.

AU - Fu, X.

AU - He, H.

AU - Lu, S.

AU - Chen, X.D.

AU - Tan, L.J.

AU - Yang, T.L.

AU - Guo, Y.

AU - Leo, P.J.

AU - Duncan, E.L.

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 - Hu, X.

AU - Das, P.M.

AU - Tian, Q.

AU - Zhu, X.Z.

AU - Papasian, C.J.

AU - Brown, M.A.

AU - Uitterlinden, A.G.

AU - Wang, Y.P.

AU - Xiang, S.

AU - Deng, H.W.

PY - 2015/8/16

Y1 - 2015/8/16

N2 - © The Author 2015. Published by Oxford University Press. All rights reserved. MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.

AB - © The Author 2015. Published by Oxford University Press. All rights reserved. MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.

U2 - 10.1093/hmg/ddv144

DO - 10.1093/hmg/ddv144

M3 - Article

SN - 0964-6906

VL - 24

SP - 4710

EP - 4727

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

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