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Hum Mol Genet. 2015 Aug 15;24(16):4710-27. doi: 10.1093/hmg/ddv144. Epub 2015 May 4.

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

Author information

1
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
2
Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P. R. China.
3
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA, Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, P. R. China.
4
Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P. R. China.
5
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
6
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia, Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
7
Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
8
Rural Clinical School, The University of Queensland, Toowoomba, Australia.
9
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia.
10
Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
11
Menzies Research Institute, University of Tasmania, Hobart, Australia.
12
Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
13
Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, P. R. China.
14
Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, USA.
15
Department of Internal Medicine and , Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands and.
16
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA, Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA.
17
Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P. R. China, hdeng2@tulane.edu xshlin@hunnu.edu.cn.
18
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA, Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P. R. China, hdeng2@tulane.edu xshlin@hunnu.edu.cn.

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.

PMID:
25941324
PMCID:
PMC4512621
DOI:
10.1093/hmg/ddv144
[Indexed for MEDLINE]
Free PMC Article

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