Fuquan Zhang, Yong Xu1, Yin Yao Shugart2, Weihua Yue3, Guoyang Qi4, Guozhen Yuan4, Zaohuo Cheng4, Jianjun Yao4, Jidong Wang4, Guoqiang Wang4, Hongbao Cao5, Wei Guo5, Zhenhe Zhou4, Zhiqiang Wang4, Lin Tian4, Chunhui Jin4, Jianmin Yuan4, Chenxing Liu3, Dai Zhang6. 1. Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China; 2. Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; Department of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD; 3. Department of Psychiatry, The Sixth Affiliated Hospital and Institute for Mental Health of Peking University/Key Laboratory of Mental Health, Ministry of Health, Beijing, China; 4. Department of Clinical Psychology, Wuxi Mental Health Center of Nanjing Medical University, Wuxi, China; 5. Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; 6. Department of Psychiatry, The Sixth Affiliated Hospital and Institute for Mental Health of Peking University/Key Laboratory of Mental Health, Ministry of Health, Beijing, China; Peking-Tsinghua Center for Life Sciences/PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China daizhang@bjmu.edu.cn.
Abstract
BACKGROUND: Previous findings are inconsistent; yet, converging evidence suggests an association between schizophrenia (SZ) and the impairment of posttranscriptional regulation of brain development through microRNA (miRNA) systems. METHODS: This study aims to (1) compare the overall frequency of 121 rare variants (RVs) in 59 genes associated with the miRNA system in genome-wide association studies (GWAS)-derived data including 768 SZ cases and 1348 healthy controls and validated in an independent GWAS data including 1802 SZ cases and 1447 controls; (2) profile genome-wide miRNA expression in blood collected from 15 early-onset SZ (EOS) cases and 15 healthy controls; and (3) construct a miRNA-messenger RNA (mRNA) regulatory network using our previous genome-wide mRNA expression data generated from a separate sample of 18 EOS cases and 12 healthy controls. RESULTS: Our findings indicate that: (1) In genes associated with the control of miRNAs, there are approximately 50% more RVs in SZ cases than in controls (P ≤ 2.62E-10); (2) The observed lower miRNA activity in EOS patients compared with the healthy controls suggests that miRNAs are abnormally downregulated; (3) There exists a predicted regulatory network among some downregulated miRNAs and some upregulated mRNAs. CONCLUSIONS: Collectively, results from all 3 lines of evidence, suggest that the genetically based dysregulation of miRNA systems undermines miRNAs' inhibitory effects, resulting in the abnormal upregulation of genome transcription in the development of SZ.
BACKGROUND: Previous findings are inconsistent; yet, converging evidence suggests an association between schizophrenia (SZ) and the impairment of posttranscriptional regulation of brain development through microRNA (miRNA) systems. METHODS: This study aims to (1) compare the overall frequency of 121 rare variants (RVs) in 59 genes associated with the miRNA system in genome-wide association studies (GWAS)-derived data including 768 SZ cases and 1348 healthy controls and validated in an independent GWAS data including 1802 SZ cases and 1447 controls; (2) profile genome-wide miRNA expression in blood collected from 15 early-onset SZ (EOS) cases and 15 healthy controls; and (3) construct a miRNA-messenger RNA (mRNA) regulatory network using our previous genome-wide mRNA expression data generated from a separate sample of 18 EOS cases and 12 healthy controls. RESULTS: Our findings indicate that: (1) In genes associated with the control of miRNAs, there are approximately 50% more RVs in SZ cases than in controls (P ≤ 2.62E-10); (2) The observed lower miRNA activity in EOS patients compared with the healthy controls suggests that miRNAs are abnormally downregulated; (3) There exists a predicted regulatory network among some downregulated miRNAs and some upregulated mRNAs. CONCLUSIONS: Collectively, results from all 3 lines of evidence, suggest that the genetically based dysregulation of miRNA systems undermines miRNAs' inhibitory effects, resulting in the abnormal upregulation of genome transcription in the development of SZ.
Authors: Manuel A Rivas; Mélissa Beaudoin; Agnes Gardet; Christine Stevens; Yashoda Sharma; Clarence K Zhang; Gabrielle Boucher; Stephan Ripke; David Ellinghaus; Noel Burtt; Tim Fennell; Andrew Kirby; Anna Latiano; Philippe Goyette; Todd Green; Jonas Halfvarson; Talin Haritunians; Joshua M Korn; Finny Kuruvilla; Caroline Lagacé; Benjamin Neale; Ken Sin Lo; Phil Schumm; Leif Törkvist; Marla C Dubinsky; Steven R Brant; Mark S Silverberg; Richard H Duerr; David Altshuler; Stacey Gabriel; Guillaume Lettre; Andre Franke; Mauro D'Amato; Dermot P B McGovern; Judy H Cho; John D Rioux; Ramnik J Xavier; Mark J Daly Journal: Nat Genet Date: 2011-10-09 Impact factor: 38.330
Authors: A L Guillozet-Bongaarts; T M Hyde; R A Dalley; M J Hawrylycz; A Henry; P R Hof; J Hohmann; A R Jones; C L Kuan; J Royall; E Shen; B Swanson; H Zeng; J E Kleinman Journal: Mol Psychiatry Date: 2013-03-26 Impact factor: 15.992
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