Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Xianglong Zhang, Department of Structural Biology, Stanford University School of Medicine
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  • Abdel Abdellaoui, Amsterdam Public Health, Vrije Universiteit, Amsterdam
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  • James Rucker, King's College London
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  • Simone de Jong, King's College London
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  • James B. Potash, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore
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  • Myrna M. Weissman, New York State Psychiatric Institute
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  • Jianxin Shi, National Cancer Institute, Bratislava, Slovakia
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  • James A. Knowles, Albert Einstein College of Medicine of Yeshiva University
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  • Carlos Pato, SUNY Downstate Medical Center
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  • Michele Pato, Division of Social and Transcultural Psychiatry, Department of Psychiatry, McGill University
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  • Janet Sobell, University of Southern California
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  • Johannes H. Smit, Vrije Universiteit, Amsterdam, Amsterdam Public Health
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  • Jouke Jan Hottenga, Amsterdam Public Health
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  • Eco J.C. de Geus, Amsterdam Public Health
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  • Cathryn M. Lewis, King's College London
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  • Henriette N. Buttenschøn
  • Nick Craddock, Cardiff University
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  • Ian Jones, Cardiff University
  • ,
  • Lisa Jones, University of Worcester
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  • Peter McGuffin, King's College London
  • ,
  • Ole Mors
  • Michael J. Owen, Cardiff University
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  • Martin Preisig, Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne
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  • Marcella Rietschel, Division of Genetic Epidemiology in Psychiatry
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  • John P. Rice, Internal Medicine, Washington University in St. Louis, School of Medicine
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  • Margarita Rivera, King's College London, Universidad de Granada
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  • Rudolf Uher, Dalhousie University
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  • Pablo V. Gejman, NorthShore University Health System and University of Chicago, University of Chicago, Chicago, Illinois.
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  • Alan R. Sanders, NorthShore University Health System and University of Chicago, University of Chicago, Chicago, Illinois.
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  • Dorret Boomsma, Amsterdam Public Health
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  • Brenda W.J.H. Penninx, Vrije Universiteit, Amsterdam, Amsterdam Public Health
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  • Gerome Breen, King's College London, The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West) at University Hospitals Bristol NHS Foundation Trust
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  • Douglas F. Levinson, Department of Structural Biology, Stanford University School of Medicine

Background: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. Methods: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. Results: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. Conclusions: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.

Original languageEnglish
JournalBiological Psychiatry
Volume85
Issue12
Pages (from-to)1065-1073
Number of pages9
ISSN0006-3223
DOIs
Publication statusPublished - Jun 2019

    Research areas

  • Copy number variation, Genetics, Genome-wide association study, Major depressive disorder, Meta-analysis, Neuroscience

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