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

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 J., Duncan, Emma L., Shen, Jie, Guo, Yan-Fang, Nicholson, Geoffrey C., Prince, Richard L., Eisman, John A., Jones, Graeme, Sambrook, Philip N., Hu, Xiang, Das, Partha M., Tian, Qing, Zhu, Xue-Zhen, Papasian, Christopher J., Brown, Matthew A., Uitterlinden, André G., Wang, Yu-Ping, Xiang, Shuanglin, & 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, 24(16), pp. 4710-4727.

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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. © The Author 2015. Published by Oxford University Press. All rights reserved.

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ID Code: 94195
Item Type: Journal Article
Refereed: Yes
Keywords: FGFRL1 protein, microRNA, unclassified drug, 3' untranslated region, Article, bone density, clinical genetics, computer model, femur neck, gene linkage disequilibrium, gene replication, genetic association, genetic conservation, genetics, genotype, hip, human, luciferase assay, lumbar spine, nonhuman, phenotype, priority journal, RNA structure, single nucleotide polymorphism, Danio rerio
DOI: 10.1093/hmg/ddv144
ISSN: 0964-6906
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 04 Apr 2016 01:47
Last Modified: 04 Apr 2016 21:19

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