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 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.
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Tianhua
T
Niu
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.
Ning
N
Liu
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Ming
M
Zhao
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.
Guie
G
Xie
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.
Lei
L
Zhang
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Jian
J
Li
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Yu-Fang
YF
Pei
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Hui
H
Shen
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Xiaoying
X
Fu
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Hao
H
He
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.
Shan
S
Lu
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.
Xiang-Ding
XD
Chen
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.
Li-Jun
LJ
Tan
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.
Tie-Lin
TL
Yang
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.
Yan
Y
Guo
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Paul J
PJ
Leo
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.
Emma L
EL
Duncan
Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
Jie
J
Shen
Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, P. R. China.
Yan-Fang
YF
Guo
Rural Clinical School, The University of Queensland, Toowoomba, Australia.
Geoffrey C
GC
Nicholson
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia.
Richard L
RL
Prince
Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
John A
JA
Eisman
Menzies Research Institute, University of Tasmania, Hobart, Australia.
Graeme
G
Jones
Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
Philip N
PN
Sambrook
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.
Xiang
X
Hu
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Partha M
PM
Das
Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Qing
Q
Tian
Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, P. R. China.
Xue-Zhen
XZ
Zhu
Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, USA.
Christopher J
CJ
Papasian
Human Genetics Group, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Matthew A
MA
Brown
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.
André G
AG
Uitterlinden
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.
Yu-Ping
YP
Wang
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.
Shuanglin
S
Xiang
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.
Hong-Wen
HW
Deng
D020413:3' Untranslated Regions; D015519:Bone Density / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011110:Polymorphism, Genetic; D051500:Receptor, Fibroblast Growth Factor, Type 5 / Q000235:genetics*
D020413:3' Untranslated Regions; C417531:FGFRL1 protein, human; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D051500:Receptor, Fibroblast Growth Factor, Type 5