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Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder

Molecular Psychiatry volume 17, pages 421–432 (2012)Cite this article

Abstract

We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset ⩽21 years (AO⩽21years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO⩽21years and AO>21years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO⩽21years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO⩽21years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO⩽21years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.

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Acknowledgements

We thank all of the patients who participated in this study. We also thank all of the probands from the community-based cohort of PopGen as well as that of the Heinz Nixdorf Recall (HNR) study, which was established with the support of the Heinz Nixdorf Foundation. The present study was supported by the German Federal Ministry of Education and Research (BMBF) within the context of the National Genome Research Network plus (NGFNplus) and the MooDS-Net (grant 01GS08144 to SC and MMN, grant 01GS08147 to MR). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. MGS was supported by the Romanian Ministry for Education and Research (grant 42151/2008 to MGS). Some of the results of this study were obtained using the program package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. We are grateful to J Sebat (Department of Psychiatry, University of California, San Diego) for his critical review of the manuscript.

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Author notes

  1. S Cichon and T W Mühleisen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    L Priebe, F A Degenhardt, S Herms, B Haenisch, M Mattheisen, M Weingarten, M Alblas, M M Nöthen, S Cichon & T W Mühleisen

  2. Institute of Human Genetics, University of Bonn, Bonn, Germany

    L Priebe, F A Degenhardt, S Herms, B Haenisch, M Mattheisen, M Weingarten, M Alblas, P Propping, M M Nöthen, S Cichon & T W Mühleisen

  3. Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany

    M Mattheisen

  4. Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany

    V Nieratschker, S Witt, R Breuer, T Paul & M Rietschel

  5. Institute for Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Essen, Germany

    S Moebus

  6. Centre National de Génotypage, Institut Génomique, Evry Cedex, France

    M Lathrop

  7. INSERM U-513, Faculté de Médecine, Créteil, France

    M Leboyer

  8. University of Paris, Faculty of Medicine, Créteil, France

    M Leboyer

  9. Department of Psychiatry, AP-HP, Albert Chenevier and Henri Mondor Hospitals, Créteil, France

    M Leboyer

  10. Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany

    S Schreiber

  11. Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania

    M Grigoroiu-Serbanescu

  12. Department of Psychiatry, University of Bonn, Bonn, Germany

    W Maier

  13. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Center Juelich, Juelich, Germany

    S Cichon

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Correspondence to S Cichon.

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Priebe, L., Degenhardt, F., Herms, S. et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol Psychiatry 17, 421–432 (2012). https://doi.org/10.1038/mp.2011.8

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