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

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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
Journal	Biological Psychiatry
Volume	85
Issue	12
Pages (from-to)	1065-1073
Number of pages	9
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2019.02.022
Publication status	Published - Jun 2019

Keywords

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

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10.1016/j.biopsych.2019.02.022

1-s2.0-S0006322319301507-mainFinal published version, 199 KBLicence: CC BY-NC-ND

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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{aad4909a89794d47853a404629e8063b,

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,

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

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts. / Zhang, Xianglong; Abdellaoui, Abdel; Rucker, James et al.
In: Biological Psychiatry, Vol. 85, No. 12, 06.2019, p. 1065-1073.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

Y1 - 2019/6

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

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

U2 - 10.1016/j.biopsych.2019.02.022

DO - 10.1016/j.biopsych.2019.02.022

M3 - Journal article

C2 - 31003785

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

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