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

Xianglong Zhang; Abdel Abdellaoui; James Rucker; Simone de Jong; James B. Potash; Myrna M. Weissman; Jianxin Shi; James A. Knowles; Carlos Pato; Michele Pato; Janet Sobell; Johannes H. Smit; Jouke Jan Hottenga; Eco J.C. de Geus; Cathryn M. Lewis; Henriette N. Buttenschøn; Nick Craddock; Ian Jones; Lisa Jones; Peter McGuffin; Ole Mors; Michael J. Owen; Martin Preisig; Marcella Rietschel; John P. Rice; Margarita Rivera; Rudolf Uher; Pablo V. Gejman; Alan R. Sanders; Dorret Boomsma; Brenda W.J.H. Penninx; Gerome Breen; Douglas F. Levinson

doi:10.1016/j.biopsych.2019.02.022

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

Xianglong Zhang, Abdel Abdellaoui, James Rucker, Simone de Jong, James B. Potash, Myrna M. Weissman, Jianxin Shi, James A. Knowles, Carlos Pato, Michele Pato, Janet Sobell, Johannes H. Smit, Jouke Jan Hottenga, Eco J.C. de Geus, Cathryn M. Lewis, Henriette N. Buttenschøn, Nick Craddock, Ian Jones, Lisa Jones, Peter McGuffinOle Mors, Michael J. Owen, Martin Preisig, Marcella Rietschel, John P. Rice, Margarita Rivera, Rudolf Uher, Pablo V. Gejman, Alan R. Sanders, Dorret Boomsma, Brenda W.J.H. Penninx, Gerome Breen, Douglas F. Levinson^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1065-1073
Number of pages	9
Journal	Biological Psychiatry
Volume	85
Issue number	12
DOIs	https://doi.org/10.1016/j.biopsych.2019.02.022
Publication status	Published - 15 Jun 2019

Funding

GenRED and GenRED II: These projects were supported by National Institute of Mental Health ( NIMH) R01 Grants MH061686 (to DFL), MH059542 (to WH Coryell), MH075131 (to WB Lawson), MH059552 (to JBP), MH059541 (to WA Scheftner) and MH060912 (to MMW). The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression . For the Molecular Genetics of Schizophrenia (MGS) control cohort from which GenRED-I controls were drawn: This work was supported primarily by the National Institutes of Health (Grant Nos. R01MH067257 [to NG Buccola], R01MH 059588 [to BJ Mowry], R01MH059571 [to PVG], R01MH059565 to [R Freedman], R01MH059587 [to F Amin], R01MH060870 [to WF Byerley], R01M H059566 [to DW Black], R01MH059586 [to JM Silverman], R01MH061675 [to DFL], R01MH060879 to [CR Cloninger], R01MH081800 [to PVG], U01MH046276 to [CR Cloninger], U01MH046289 [to C Kaufmann], U01MH046318 [to MT Tsuang], U01MH079469 to [PVG], and U01MH079470 to [DFL]), the Genetic Association Information Network (GAIN, for genotyping of half of the EA sample), and The Paul Michael Donovan Charitable Foundation . Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT (to S Gabriel and DB Mirel), supported by NIH Grant No. U54RR020278 . We are grateful to Knowledge Networks (Menlo Park, CA) for assistance in collecting the control data set. NESDA/NTR: The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. Funding was from: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10002 , 904-61-193 , 480-04-004 , 400-05-717 , 912-100-20 ; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002 ); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University’s Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/ RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community’s Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). CM Middeldorp was supported by the Netherlands Organization for Scientific Research (NOW-VENI grant 916-76-125 ). RADIANT: 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 ( http://www.chairs-chaires.gc.ca/ ). The Genome Based Therapeutic Drugs for Depression study was funded by a European Commission Framework 6 grant, European Commission Contract Reference LSHB-CT-2 003-503428, and GlaxoSmithKline. Genotyping was performed at the Centre Nationale De Genotypage, Evry, Paris. We acknowledge the contribution of phase 2 of the Wellcome Trust Case Control Consortium in providing access to control datasets from the 1958 British birth cohort and the National Blood Service cohort. We thank Stephan Sanders from the University of California at San Francisco for his assistance using CNVision. We also thank the individuals who participated in these projects and to the many clinicians who facilitated or contributed to them. Availability of Data and Biomaterials: Biomaterials and clinical data are available from the NIMH repository ( https://nimhgenetics.org ) for the GenRED cases (the GenRED1 cohort includes the family-based linkage cohort and part of the subsequent case collection; the GenRED2 cohort includes the remainder of the case collection); for the MGS controls; and for Genomic Psychiatry Cohort controls, including the Mayo Clinic controls. The authors report no biomedical financial interests or potential conflicts of interest.

Funders	Funder number
7th European Community Framework Programme
Biomedical Research Centre for Mental Health
Broad Institute of Harvard
Center for Medical Systems Biology
DFL
ENGAGE	HEALTH-F4-2007-201413
European Commission Framework 6	LSHB-CT-2 003-503428
European Community's Seventh Framework Program
European Community’s Seventh Framework Program	FP7/2007-2013
European Science Council	230374
Foundation Trust
Institute of Psychiatry
NHS
NOW-VENI
National Blood Service
Netherlands Organization for Scientific Research
Netherlands Twin Register
South London and Maudsley National Health Service
Spinozapremie	10-000-1002, 56-464-14192
The Paul Michael Donovan Charitable Foundation
United Kingdom Medical Research Council
VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam
VU University’s Institutes for Health and Care Research and Neuroscience Campus Amsterdam	2008.024
National Institutes of Health	R01M H059566, R01MH 059588
National Institute of Mental Health	R01MH059571, R01MH059586, R01MH061675, U01MH079469, R01MH060870, R01MH059565, R01MH059587, R01MH067257, R01MH060879, MH059541, MH059552, R01MH081802, U54RR020278, R01MH081800, MH059542, U01MH046289, MH061686, U01MH046276, MH060912, U01MH046318, MH075131, U01MH079470
Mayo Clinic
University of California
North Carolina GlaxoSmithKline Foundation	G0701420
National Institute on Disability and Rehabilitation Research
Massachusetts Institute of Technology
King’s College London
South London and Maudsley NHS Foundation Trust
National Alliance for Research on Schizophrenia and Depression
Wellcome Trust	086635
National Institute for Health Research
King's College London
European Commission	115008
European Science Foundation	EU/QLRT-2001-01254
Canada Research Chairs
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	916-76-125, 480-04-004, 912-100-20, 904-61-090, 400-05-717, 985-10002, 904-61-193
Axencia Galega de Innovación
Norges Idrettshøgskole

Keywords

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

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biopsych.2019.02.022

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Cite this

Zhang, X., Abdellaoui, A., Rucker, J., de Jong, S., Potash, J. B., Weissman, M. M., Shi, J., Knowles, J. A., Pato, C., Pato, M., Sobell, J., Smit, J. H., Hottenga, J. J., de Geus, E. J. C., Lewis, C. M., Buttenschøn, H. N., Craddock, N., Jones, I., Jones, L., ... Levinson, D. F. (2019). Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts. Biological Psychiatry, 85(12), 1065-1073. https://doi.org/10.1016/j.biopsych.2019.02.022

@article{893b97a738c84c6fbd54b87f6763a445,

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

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",

author = "Xianglong Zhang and Abdel Abdellaoui and James Rucker and {de Jong}, Simone and Potash, {James B.} and Weissman, {Myrna M.} and Jianxin Shi and Knowles, {James A.} and Carlos Pato and Michele Pato and Janet Sobell and Smit, {Johannes H.} and Hottenga, {Jouke Jan} and {de Geus}, {Eco J.C.} and Lewis, {Cathryn M.} and Buttensch{\o}n, {Henriette N.} and Nick Craddock and Ian Jones and Lisa Jones and Peter McGuffin and Ole Mors and Owen, {Michael J.} and Martin Preisig and Marcella Rietschel and Rice, {John P.} and Margarita Rivera and Rudolf Uher and Gejman, {Pablo V.} and Sanders, {Alan R.} and Dorret Boomsma and Penninx, {Brenda W.J.H.} and Gerome Breen and Levinson, {Douglas F.}",

year = "2019",

month = jun,

day = "15",

doi = "10.1016/j.biopsych.2019.02.022",

language = "English",

volume = "85",

pages = "1065--1073",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "12",

}

Zhang, X, Abdellaoui, A, Rucker, J, de Jong, S, Potash, JB, Weissman, MM, Shi, J, Knowles, JA, Pato, C, Pato, M, Sobell, J, Smit, JH, Hottenga, JJ , de Geus, EJC, Lewis, CM, Buttenschøn, HN, Craddock, N, Jones, I, Jones, L, McGuffin, P, Mors, O, Owen, MJ, Preisig, M, Rietschel, M, Rice, JP, Rivera, M, Uher, R, Gejman, PV, Sanders, AR, Boomsma, D, Penninx, BWJH, Breen, G & Levinson, DF 2019, 'Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts', Biological Psychiatry, vol. 85, no. 12, pp. 1065-1073. https://doi.org/10.1016/j.biopsych.2019.02.022

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.

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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UR - http://www.scopus.com/inward/citedby.url?scp=85063186192&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2019.02.022

DO - 10.1016/j.biopsych.2019.02.022

M3 - Article

AN - SCOPUS:85063186192

SN - 0006-3223

VL - 85

SP - 1065

EP - 1073

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 12

ER -

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

Abstract

Funding

Keywords

Cohort Studies

UN SDGs

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