TY - JOUR
T1 - Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts
AU - Zhang, Xianglong
AU - Abdellaoui, Abdel
AU - Rucker, James
AU - de Jong, Simone
AU - Potash, James B.
AU - Weissman, Myrna M.
AU - Shi, Jianxin
AU - Knowles, James A.
AU - Pato, Carlos
AU - Pato, Michele
AU - Sobell, Janet
AU - Smit, Johannes H.
AU - Hottenga, Jouke Jan
AU - de Geus, Eco J.C.
AU - Lewis, Cathryn M.
AU - Buttenschøn, Henriette N.
AU - Craddock, Nick
AU - Jones, Ian
AU - Jones, Lisa
AU - McGuffin, Peter
AU - Mors, Ole
AU - Owen, Michael J.
AU - Preisig, Martin
AU - Rietschel, Marcella
AU - Rice, John P.
AU - Rivera, Margarita
AU - Uher, Rudolf
AU - Gejman, Pablo V.
AU - Sanders, Alan R.
AU - Boomsma, Dorret
AU - Penninx, Brenda W.J.H.
AU - Breen, Gerome
AU - Levinson, Douglas F.
N1 - Copyright © 2019 Society of Biological Psychiatry. All rights reserved.
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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.
AB - 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.
KW - Copy number variation
KW - Genetics
KW - Genome-wide association study
KW - Major depressive disorder
KW - Meta-analysis
KW - Neuroscience
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U2 - https://doi.org/10.1016/j.biopsych.2019.02.022
DO - https://doi.org/10.1016/j.biopsych.2019.02.022
M3 - Article
C2 - 31003785
SN - 0006-3223
VL - 85
SP - 1065
EP - 1073
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 12
ER -