Rare duplications in RB1CC1 are associated with schizophrenia in large datasets from Europe. F. Degenhardt1,2, M. A. Pfohl1,2, L. Lennertz4, L. Priebe1,2, J. Strohmaier3, S. H. Witt3, A. Hofmann1,2, T. Becker5,6, R. Mössner4, W. Maier4,5, I. Nenadic7, S. Meier3, J. Buizer-Voskamp8,9, R. A. Ophoff10,11, D. Rujescu12,13, I. Giegling12,13, A. Ingason13, M. Wagner4, A. Meyer-Lindenberg14, H. Walter15, S. Moebus16, A. Corvin17, H. Stefánsson18, T. G. Schulze3,19, M. Rietschel3, S. Cichon1,2,20,21, M. M. Nöthen1,2,5, GROUP Consortium, Wellcome Trust Case Control Consortium 2; International Schizophrenia Consortium 1) Institute of Human Genetics, University of Bonn, Bonn, Germany; 2) Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; 3) Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany; 4) Department of Psychiatry, University of Bonn, Bonn, Germany; 5) German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; 6) Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany; 7) Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany; 8) Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands; 9) Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 10) Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; 11) Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California Los Angeles, Los Angeles, California, USA; 12) Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany; 13) Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany; 14) Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 15) Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Berlin, Germany; 16) Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen, Germany; 17) Department of Psychiatry, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; 18) deCODE Genetics, IS-101 Reykjavik, Iceland; 19) Section of Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany; 20) Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Juelich, Germany; 21) Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.

   Schizophrenia is a severe neuropsychiatric disorder with heritability estimates of ~80%. Recently, the first exome-sequencing studies (NGS) in patients with schizophrenia were published. They provided evidence that de novo mutations were more frequent in patients compared to controls (Girard et al., 2011, Xu et al., 2011). These results suggested that de novo mutations contribute to the risk of developing schizophrenia. However, a large number of genes were hit by de novo mutations and therefore it is not easy to pinpoint specific genes as actually being relevant for the disease process. Support for a specific gene can be provided by the identification of additional alterations - including copy number variants (CNVs) - in independent study cohorts. We screened the genome-wide SNP array data from 1,637 patients with schizophrenia and 1,627 controls for the presence of CNVs in 55 candidate genes, suggested from NGS studies. Duplications in RB1CC1 on chromosome 8 were overrepresented in patients. The CNVs were technically verified using quantitative PCR. The duplications were followed-up in independent European samples. In the combined analysis, comprising of 8,461 patients and 112,871 controls, duplications in RB1CC1 were found to be associated with schizophrenia (P = 1.29 x 10-5; odds ratio = 8.58). To obtain additional evidence for RB1CC1 being a strong candidate gene for schizophrenia we are currently sequencing selected regions of RB1CC1 for the presence of rare mutations in 2,200 patients. RB1CC1 is a brain expressed gene and has been implicated in cell cycle progression and neurodegeneration. Our study is the first to provide evidence that rare duplications in RB1CC1 are a risk factor for schizophrenia. Results from our targeted resequencing of RB1CC1 wil be presented.

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