Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies
Journal article
Niu, Tianhua, Liu, Ning, Zhao, Ming, Xie, Guie, Zhang, Lei, Li, Jian, Pei, Yu-Fang, Shen, Hui, Fu, Xiaoying, He, Hao, Lu, Shan, Chen, Xiang-Ding, Tan, Li-Jun, Yang, Tie-Lin, Guo, Yan, Leo, Paul, Duncan, Emma, Shen, Jie, Guo, Yan-Fang, ... Deng, Hong-Wen. (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. https://doi.org/10.1093/hmg/ddv144
Authors | Niu, Tianhua, Liu, Ning, Zhao, Ming, Xie, Guie, Zhang, Lei, Li, Jian, Pei, Yu-Fang, Shen, Hui, Fu, Xiaoying, He, Hao, Lu, Shan, Chen, Xiang-Ding, Tan, Li-Jun, Yang, Tie-Lin, Guo, Yan, Leo, Paul, Duncan, Emma, Shen, Jie, Guo, Yan-Fang, Nicholson, Geoffrey, Prince, Richard, Eisman, John, Jones, Graeme, Sambrook, Philip, Hu, Xiang, Das, Partha, Tian, Qing, Zhu, Xue-Zhen, Papasian, Christopher, Brown, Matthew, Uitterlinden, Andre, Wang, Yu-Ping, Xiang, Shuanglin and Deng, Hong-Wen |
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Abstract | 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. |
Year | 2015 |
Journal | Human Molecular Genetics |
ISSN | 0964-6906 |
Digital Object Identifier (DOI) | https://doi.org/10.1093/hmg/ddv144 |
Page range | 4710 - 4727 |
Research Group | Institute for Health and Ageing |
Publisher's version | File Access Level Controlled |
https://acuresearchbank.acu.edu.au/item/897v2/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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