Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies
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.
|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.|
|Publisher Name||HUMAN MOLECULAR GENETICS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25941324|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12892|