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Transl Psychiatry. 2013 Nov 26;3:e326. doi: 10.1038/tp.2013.101.

Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.

Author information

1
1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
2
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
3
Department of Psychiatry, University of Bonn, Bonn, Germany.
4
1] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany [2] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
5
1] Department of Psychiatry, University of Bonn, Bonn, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
6
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
7
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.
8
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.
9
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.
10
1] Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
11
Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
12
Centre de Génétique chromosomique, GHICL, Hôpital St-Vincent de Paul, Lille, France.
13
Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, France.
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
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.

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.

PMID:
26151896
PMCID:
PMC3849960
DOI:
10.1038/tp.2013.101
[Indexed for MEDLINE]
Free PMC Article

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