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Genome-wide burden of rare short deletions is enriched in major depressive disorder in four cohorts

Zhang, Xianglong, Abdellaoui, Abdel, Rucker, James, de Jong, Simone, Potash, James B., Weissman, Myrna M., Shi, Jianxin, Knowles, James A., Pato, Carlos, Pato, Michele, Sobell, Janet, Smit, Johannes H., Hottenga, Jouke-Jan, de Geus, Eco J.C., Lewis, Cathryn M., Buttenschøn, Henriette N., Craddock, Nick ORCID:, Jones, Ian ORCID:, Jones, Lisa ORCID:, McGuffin, Peter, Mors, Ole, Owen, Michael J. ORCID:, Preisig, Martin, Rietschel, Marcella, Rice, John P., Rivera, Margarita, Uher, Rudolf, Gejman, Pablo V., Sanders, Alan R., Boomsma, Dorret, Penninx, Brenda W.J.H., Breen, Gerome and Levinson, Douglas F. 2019. Genome-wide burden of rare short deletions is enriched in major depressive disorder in four cohorts. Biological Psychiatry 85 (12) , pp. 1065-1073. 10.1016/j.biopsych.2019.02.022

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 13 May 2019
Date of Acceptance: 19 February 2019
Last Modified: 04 May 2023 10:06

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