Niu, T., Liu, N., Zhao, M., Xie, G., Zhang, L., Li, J., Pei, Y., Shen, H., Fu, X., He, H., Lu, S., Chen, X., Tan, L., Yang, T., Guo, Y., Leo, P., Duncan, E., Shen, J., Guo, Y., Nicholson, G., Prince, R., Eisman, J., Jones, G., Sambrook, P., Hu, X., Das, P., Tian, Q., Zhu, X., Papasian, C., Brown, M., Uitterlinden, A., Wang, Y., Xiang, S. & Deng, H. (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,(16), 4710-4727. Retrieved from https://doi.org/10.1093/hmg/ddv144
MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA 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 seven 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 andPRR5 rs3213550 as top signals for FN-BMD (P = 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 = 5.08 × 10−3) at α = 0.10/11 = 9.09 × 10-3. PRR5rs3213550 was also selected based on biological significance. In stage IIIde novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 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 = 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.
Institute for Health and Ageing