PMID- 29499969 OWN - NLM STAT- MEDLINE DCOM- 20190311 LR - 20190311 IS - 1573-2509 (Electronic) IS - 0920-9964 (Linking) VI - 199 DP - 2018 Sep TI - Schizophrenia-associated rs4702 G allele-specific downregulation of FURIN expression by miR-338-3p reduces BDNF production. PG - 176-180 LID - S0920-9964(18)30116-6 [pii] LID - 10.1016/j.schres.2018.02.040 [doi] AB - Genome-wide association studies (GWAS) reveal numerous schizophrenia (SCZ)-associated single-nucleotide polymorphisms (SNPs); however, functional characterizations of the risk variants remain to be established. Using data from 108 SCZ GWAS loci, we performed systematic miRNA binding site screening of 128 SCZ-associated SNPs and found that 2 out of 3 SNPs located in the 3'UTR were predicted to alter 3 miRNAs' binding sites in 2 target genes. Of the identified SNPs, the most genome-wide significant SNP rs4702 (A/G) in the FURIN 3'UTR, previously identified as an SCZ-associated cis-expression quantitative trait loci (downregulated by the risk G allele), is located in the binding site of miR-338-3p in the presence of the risk G allele. Allele-specific downregulation of FURIN by miR-338-3p was validated with a luciferase reporter assay. Furthermore, we demonstrated that miR-338-3p-mediated FURIN inhibition reduced brain-derived neurotrophic factor (BDNF) maturation and secretion in human embryonic kidney 293T cells. Our data reveal that schizophrenia-associated rs4702 G allele-specific downregulation of FURIN by miR-338-3p reduces mature BDNF production. These data help elucidate the mechanism of genetic predisposition toward schizophrenia or other neurodevelopmental diseases. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Hou, Yu AU - Hou Y AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Department of Pediatric Neurology, Affiliated BaYi Children's Hospital, PLA Army General Hospital, Beijing, China. FAU - Liang, Wenquan AU - Liang W AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong, China. FAU - Zhang, Jian AU - Zhang J AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China. FAU - Li, Qiyang AU - Li Q AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China. FAU - Ou, Haiyan AU - Ou H AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China. FAU - Wang, Zhongju AU - Wang Z AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China. FAU - Li, Shufen AU - Li S AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong, China. FAU - Huang, Xingbing AU - Huang X AD - Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China. FAU - Zhao, Cunyou AU - Zhao C AD - Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong, China. Electronic address: cyzhao@smu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180228 PL - Netherlands TA - Schizophr Res JT - Schizophrenia research JID - 8804207 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (MIRN338 microRNA, human) RN - 0 (MicroRNAs) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 3.4.21.75 (FURIN protein, human) RN - EC 3.4.21.75 (Furin) SB - IM MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Computational Biology MH - Down-Regulation MH - Furin/*genetics/*metabolism MH - Genetic Predisposition to Disease MH - Genome-Wide Association Study MH - HEK293 Cells MH - Humans MH - MicroRNAs/*metabolism MH - Polymorphism, Single Nucleotide MH - Schizophrenia/*genetics/*metabolism OTO - NOTNLM OT - BDNF OT - FURIN OT - Genome-wide association study OT - Schizophrenia OT - Single-nucleotide polymorphism OT - miRNA EDAT- 2018/03/04 06:00 MHDA- 2019/03/12 06:00 CRDT- 2018/03/04 06:00 PHST- 2017/03/24 00:00 [received] PHST- 2018/02/21 00:00 [revised] PHST- 2018/02/21 00:00 [accepted] PHST- 2018/03/04 06:00 [pubmed] PHST- 2019/03/12 06:00 [medline] PHST- 2018/03/04 06:00 [entrez] AID - S0920-9964(18)30116-6 [pii] AID - 10.1016/j.schres.2018.02.040 [doi] PST - ppublish SO - Schizophr Res. 2018 Sep;199:176-180. doi: 10.1016/j.schres.2018.02.040. Epub 2018 Feb 28.