title: Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.
abstract: Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Priebe
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Meier
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Lennertz
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Streit
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: S H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: 1] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany [2] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Becker
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mössner
authors.affiliation: 1] Department of Psychiatry, University of Bonn, Bonn, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Nenadic
authors.affiliation: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Sauer
authors.affiliation: 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute for Genomic Mathematics, University of Bonn, Bonn, Germany [3] Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: 1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Buizer-Voskamp
authors.affiliation: 1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA [3] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: 1] Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: 1] Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Giegling
authors.affiliation: Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ingason
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Centre de Génétique chromosomique, GHICL, Hôpital St-Vincent de Paul, Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Delobel
authors.affiliation: Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Walter
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Moebus
authors.affiliation: Department of Psychiatry, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Corvin
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [3] Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Juelich, Germany [4] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
mesh_terms: D000328:Adult; D000368:Aged; D000071183:Autophagy-Related Proteins; D005060:Europe; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D000071183:Autophagy-Related Proteins; C407704:RB1CC1 protein, human; D011505:Protein-Tyrosine Kinases