title: Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia.
abstract: BACKGROUND
  Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185.
  
  
  METHODS
  We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082).
  
  
  RESULTS
  In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia.
  
  
  CONCLUSIONS
  Power to detect rare variant associations was limited.
  
  
  CONCLUSIONS
  Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: F B
authors.initials: FB
authors.lastname: Basmanav
authors.affiliation: The Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, the The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, and Copenhagen, Denmark, and the Department of Genomics Mathematics, University of Bonn, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Böhmer
authors.affiliation: The Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Hollegaard
authors.affiliation: The Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Janson
authors.affiliation: The Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Strengman
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Priebe
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: The Institute of Human Genetics, University of Bonn, the Department of Genomics, Life and Brain Center, Bonn, Germany, and the Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: The Institute of Human Genetics, University of Bonn, the Department of Genomics, Life and Brain Center, Bonn, Germany, and the Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: The Department of Psychiatry, University of Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: The Department of Psychiatry, University of Bonn, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.affiliation: The Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: The Center for Neurobehavioral Genetics, University of California Los Angeles, USA and the Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht, the Netherlands.
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: The Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Preben B
authors.initials: PB
authors.lastname: Mortensen
authors.affiliation: The Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, the The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, and the Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: The Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Frank
authors.affiliation: The Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: The Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: The Institute of Molecular Psychiatry, University of Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: The Institute of Molecular Psychiatry, University of Bonn, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Miró
authors.affiliation: The Institute of Human Genetics, University of Bonn, the Department of Genomics, Life and Brain Center, Bonn, the Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Germany and the Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006571:Heterocyclic Compounds; D006801:Humans; D017403:In Situ Hybridization; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008868:Microtubule Proteins; D020812:Receptor, trkC / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: C091054:3-decyl-1,5,8-triazacyclodecane-2,4-dione; D006571:Heterocyclic Compounds; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; D008868:Microtubule Proteins; C578934:Mirn185 microRNA, mouse; D000123:Acetyltransferases; C583619:ATAT1 protein, mouse; D020812:Receptor, trkC