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 and 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: 4710-4727. doi:10.1093/hmg/ddv144


Author 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
Title Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies
Formatted title
Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
0964-6906
Publication date 2015-08-15
Year available 2015
Sub-type Article (original research)
DOI 10.1093/hmg/ddv144
Open Access Status Not Open Access
Volume 24
Issue 16
Start page 4710
End page 4727
Total pages 18
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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 and PRR5 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. 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 = 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.
Keyword MicroRNAs
Genome-wide association (GWA) scan
Polymorphism
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID S30501
P50AR055081
N01-HC-25195
N02-HL-64278
P01-AG018397
N01WH22110
U01 HG004790
175.010.2005.011
014-93-015
050-060-810
2001-2003-348-6111-221
511132
569807
31100902
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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