PUBLICATION
Identification of a Novel FGFRL1 MicroRNA Target Site Polymorphism for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies
- Authors
- 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., Nicholson, G.C., Prince, R.L., Eisman, J.A., Jones, G., Sambrook, P.N., Hu, X., Das, P.M., Tian, Q., Zhu, X.Z., Papasian, C.J., Brown, M.A., Uitterlinden, A.G., Wang, Y.P., Xiang, S., Deng, H.W.
- ID
- ZDB-PUB-150506-4
- Date
- 2015
- Source
- Human molecular genetics 24(16): 4710-27 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- 3' Untranslated Regions*
- Bone Density/genetics*
- Female
- Genetic Loci*
- Genome-Wide Association Study
- Humans
- Male
- MicroRNAs/genetics*
- Polymorphism, Genetic*
- Receptor, Fibroblast Growth Factor, Type 5/genetics*
- PubMed
- 25941324 Full text @ Hum. Mol. Genet.
Citation
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., Nicholson, G.C., Prince, R.L., Eisman, J.A., Jones, G., Sambrook, P.N., Hu, X., Das, P.M., Tian, Q., Zhu, X.Z., Papasian, C.J., Brown, M.A., Uitterlinden, A.G., Wang, Y.P., Xiang, S., 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):4710-27.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping