@misc{10481/61562,
year = {2019},
url = {http://hdl.handle.net/10481/61562},
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.},
organization = {This work was supported by a joint grant from the United
Kingdom Medical Research Council and GlaxoSmithKline (Grant No.
G0701420) and the National Institute for Health Research (NIHR) Biomedical
Research Centre for Mental Health at South London and Maudsley National
Health Service (NHS) Foundation Trust and Institute of Psychiatry, King’s
College London. This work presents independent research in part funded by
the NIHR. The views expressed are those of the authors and not necessarily
those of the NHS, the NIHR, or the Department of Health. This work was also
supported by the Wellcome Trust Grant No. 086635 (JJHR); 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 (SC-W); a Marie Curie Intra-European Fellowship within the
7th European Community Framework Programme; European Commission
Grant Agreement No. 115008); and Canada Research Chairs program},
publisher = {Elsevier Inc.},
keywords = {Copy number variation},
keywords = {Genome-wide association study (GWAS)},
keywords = {Major depressive disorder},
keywords = {Neuroscience},
title = {Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts},
doi = {10.1016/j.biopsych.2019.02.022},
author = {Zang, Xianglong and Rivera Sánchez, Margarita},
}