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Genome-wide association analysis of copy number variation in recurrent depressive disorder

Molecular Psychiatry volume 18, pages 183–189 (2013)Cite this article

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Abstract

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10−6, odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13–1.37)) and to screened controls (P=5.6 × 10−4, OR=1.52 (95% CI 1.20–1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

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Acknowledgements

This study was funded by a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420). James Rucker was supported by a fellowship from the Wellcome Trust (086635). Alexandra Schosser was supported by the Erwin-Schroedinger Fellowship (J2647) of the Austrian Science Funds. Alexandra Schosser, Inti Pedroso and Sarah Cohen-Woods received financial support from the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London. Margarita Rivera was supported by a Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme. The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428 and GlaxoSmithKline contributed by funding an add-on project in the London centre. The population-based study in Lausanne was supported by three grants from the Swiss National Science Foundation (No. 3200B0-105993, No. 3200B0-118308, No. 33CSCO-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery Verona, R&D). Rudolf Uher and Peter McGuffin are supported by a grant from the European Commission (Grant Agreement No. 115008). Genotyping was performed at the Centre Nationale De Genotypage, Evry, Paris, with acknowledgement to Simon Heath, Ivo Gut and Mark Lathrop. We acknowledge the contribution of phase 2 of the Wellcome Trust Case Control Consortium in providing access to control data sets from the 1958 British birth cohort and the national blood service cohort.

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Authors and Affiliations

  1. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK

    J J H Rucker, G Breen, I Pedroso, C M Lewis, S Cohen-Woods, R Uher, A Schosser, M Rivera, K J Aitchison, A E Farmer, I W Craig & P McGuffin

  2. National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust and Institute of Psychiatry, King's College London, London, UK

    G Breen, I Pedroso, A E Farmer & P McGuffin

  3. The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, MaRS Centre–East Tower, Toronto, Ontario, Canada

    D Pinto & S W Scherer

  4. Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria

    A Schosser

  5. CIBERSAM, University of Granada, Section of Psychiatry, Institute of Neurosciences, Biomedical Research Centre (CIBM), Granada, Spain

    M Rivera

  6. MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK

    N Craddock, M J Owen & I Jones

  7. Department of Psychiatry, University of Birmingham, Birmingham, UK

    L Jones

  8. Barts and The London Medical School, Queen Mary University of London, London, UK

    A Korszun

  9. Medical Genetics GlaxoSmithKline, Verona, Italy

    P Muglia & M R Barnes

  10. Medical Genetics GlaxoSmithKline, Greenford, UK

    P Muglia & M R Barnes

  11. Department of Adult Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland

    M Preisig

  12. Centre of Psychiatric Research, Aarhus University Hospital, Risskov, Denmark

    O Mors

  13. Department of Psychiatry, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

    M Gill

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

    W Maier

  15. Department of Psychiatry, Washington University, St Louis, MO, USA

    J Rice

  16. Central Institute of Mental Health, Mannheim, Germany

    M Rietschel

  17. Max Planck Institute of Psychiatry, Munich, Germany

    F Holsboer

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  1. J J H Rucker
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Corresponding author

Correspondence to J J H Rucker.

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Competing interests

The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report; however, Pierandrea Muglia and Michael Barnes were employed by GSK when the research was performed. James Rucker, Gerome Breen and Peter McGuffin had full access to all data in the study and had final responsibility for the decision to submit for publication. Katherine Aitchison, Anne Farmer and Peter McGuffin have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including GlaxoSmithKline. Anne Farmer has received travel and subsistence from GlaxoSmithKline to attend principal investigator planning, training and inter-rater reliability meetings. Katherine Aitchison also declares interests through Advisory Boards for Johnson & Johnson, Lundbeck, Roche Diagnostics, and Bristol-Myers Squibb; membership of Bristol-Myers Squibb UK Steering group 2003 to present; consultancy work for Roche Diagnostics, Johnson & Johnson Pharmaceutical Research and Development, Lundbeck, and Bristol-Myers Squibb Pharmaceuticals Limited; grants awarded by Johnson & Johnson Pharmaceutical Research & Development, Bristol-Myers Squibb Pharmaceuticals Limited, and E Merck Pharmaceuticals. All other authors declare no conflicts of interest.

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Rucker, J., Breen, G., Pinto, D. et al. Genome-wide association analysis of copy number variation in recurrent depressive disorder. Mol Psychiatry 18, 183–189 (2013). https://doi.org/10.1038/mp.2011.144

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