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Biol Psychiatry. 2019 Jun 15;85(12):1065-1073. doi: 10.1016/j.biopsych.2019.02.022. Epub 2019 Mar 13.

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Department of Genetics, Stanford University School of Medicine, Stanford, California.
2
Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands; Department of Psychiatry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
3
The Institute of Psychiatry, King's College London, London, United Kingdom.
4
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, New York.
6
Division of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute, Bethesda, Maryland.
7
Department of Cell Biology, Brooklyn, New York.
8
State University of New York Downstate Medical Center College of Medicine, Brooklyn, New York.
9
Department of Psychiatry, Brooklyn, New York.
10
Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, California.
11
Amsterdam Universitair Medische Centra, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam Public Health and GGz inGeest, Amsterdam, the Netherlands.
12
Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
13
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
14
Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark; Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
15
Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
16
Institute of Health and Society, University of Worcester, Worcester, United Kingdom.
17
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom.
18
Psychosis Research Unit, Aarhus University Hospital Risskov, Aarhus, Denmark.
19
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
20
Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
21
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
22
Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri.
23
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom; Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
24
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
25
Center for Psychiatric Genetics, NorthShore University HealthSystem, Chicago, Illinois; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois.
26
MRC Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Center for Mental Health, King's College London, London, United Kingdom.
27
Department of Genetics, Stanford University School of Medicine, Stanford, California. Electronic address: dflev@stanford.edu.

Abstract

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.

KEYWORDS:

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

PMID:
31003785
DOI:
10.1016/j.biopsych.2019.02.022
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