Phenotypic association analyses with copy number variation in recurrent depressive disorder

James J.h. Rucker; Katherine E. Tansey; Margarita Rivera; Dalila Pinto; Sarah Cohen-woods; Rudolf Uher; Katherine J. Aitchison; Nick Craddock; Michael J. Owen; Lisa Jones; Ian Jones; Ania Korszun; Michael R. Barnes; Martin Preisig; Ole Mors; Wolfgang Maier; John Rice; Marcella Rietschel; Florian Holsboer; Anne E. Farmer; Ian W. Craig; Stephen W. Scherer; Peter Mcguffin; Gerome Breen

doi:10.1016/j.biopsych.2015.02.025

Phenotypic association analyses with copy number variation in recurrent depressive disorder

James J.h. Rucker, Katherine E. Tansey, Margarita Rivera, Dalila Pinto, Sarah Cohen-woods, Rudolf Uher, Katherine J. Aitchison, Nick Craddock, Michael J. Owen, Lisa Jones, Ian Jones, Ania Korszun, Michael R. Barnes, Martin Preisig, Ole Mors, Wolfgang Maier, John Rice, Marcella Rietschel, Florian Holsboer, Anne E. FarmerIan W. Craig, Stephen W. Scherer, Peter Mcguffin, Gerome Breen

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Abstract

Background
Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.
Methods
In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.
Results
We found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).
Conclusions
After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Original language	English
Journal	Biological Psychiatry
Early online date	25 Feb 2015
DOIs	https://doi.org/10.1016/j.biopsych.2015.02.025
Publication status	E-pub ahead of print - 25 Feb 2015

Keywords

Affective Disorders
Copy Number Variation
Depression
Genetics
Phenotypes

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10.1016/j.biopsych.2015.02.025

Rucker_et_al_Phenotypic_association_analyses_Biological_Psychiatry_2015
NOTICE: this is the author’s version of a work that was accepted for publication. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published as James J.H. Rucker M.D., M.R.C., Psych., Ph.D., Katherine E. Tansey Ph.D., Margarita Rivera Ph.D., Dalila Pinto Ph.D, Sarah Cohen-Woods Ph.D., Rudolf Uher M.D., Katherine J. Aitchison M.D., M.R.C.Psych., Ph.D., Nick Craddock F.R.C.Psych., F.Med.Sci., Ph.D., Michael J. Owen F.R.C.Psych., F. Med.Sci., Ph.D., Lisa Jones Ph.D., et. al, Phenotypic Association Analyses With Copy Number Variation In Recurrent Depressive Disorder, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2015.02.025
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Rucker, J. J. H., Tansey, K. E., Rivera, M., Pinto, D., Cohen-woods, S., Uher, R., Aitchison, K. J., Craddock, N., Owen, M. J., Jones, L., Jones, I., Korszun, A., Barnes, M. R., Preisig, M., Mors, O., Maier, W., Rice, J., Rietschel, M., Holsboer, F., ... Breen, G. (2015). Phenotypic association analyses with copy number variation in recurrent depressive disorder. Biological Psychiatry. Advance online publication. https://doi.org/10.1016/j.biopsych.2015.02.025

@article{5f0f2e16f54742c19611d8c3665039b7,

title = "Phenotypic association analyses with copy number variation in recurrent depressive disorder",

abstract = "BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.MethodsIn this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.ResultsWe found an enrichment of Turner{\textquoteright}s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.",

keywords = "Affective Disorders, Copy Number Variation, Depression, Genetics, Phenotypes",

author = "Rucker, {James J.h.} and Tansey, {Katherine E.} and Margarita Rivera and Dalila Pinto and Sarah Cohen-woods and Rudolf Uher and Aitchison, {Katherine J.} and Nick Craddock and Owen, {Michael J.} and Lisa Jones and Ian Jones and Ania Korszun and Barnes, {Michael R.} and Martin Preisig and Ole Mors and Wolfgang Maier and John Rice and Marcella Rietschel and Florian Holsboer and Farmer, {Anne E.} and Craig, {Ian W.} and Scherer, {Stephen W.} and Peter Mcguffin and Gerome Breen",

year = "2015",

month = feb,

day = "25",

doi = "10.1016/j.biopsych.2015.02.025",

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

}

Rucker, JJH, Tansey, KE, Rivera, M, Pinto, D, Cohen-woods, S, Uher, R, Aitchison, KJ, Craddock, N, Owen, MJ, Jones, L, Jones, I, Korszun, A, Barnes, MR, Preisig, M, Mors, O, Maier, W, Rice, J, Rietschel, M, Holsboer, F, Farmer, AE, Craig, IW, Scherer, SW, Mcguffin, P & Breen, G 2015, 'Phenotypic association analyses with copy number variation in recurrent depressive disorder', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2015.02.025

TY - JOUR

T1 - Phenotypic association analyses with copy number variation in recurrent depressive disorder

AU - Rucker, James J.h.

AU - Tansey, Katherine E.

AU - Rivera, Margarita

AU - Pinto, Dalila

AU - Cohen-woods, Sarah

AU - Uher, Rudolf

AU - Aitchison, Katherine J.

AU - Craddock, Nick

AU - Owen, Michael J.

AU - Jones, Lisa

AU - Jones, Ian

AU - Korszun, Ania

AU - Barnes, Michael R.

AU - Preisig, Martin

AU - Mors, Ole

AU - Maier, Wolfgang

AU - Rice, John

AU - Rietschel, Marcella

AU - Holsboer, Florian

AU - Farmer, Anne E.

AU - Craig, Ian W.

AU - Scherer, Stephen W.

AU - Mcguffin, Peter

AU - Breen, Gerome

PY - 2015/2/25

Y1 - 2015/2/25

N2 - BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.MethodsIn this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.ResultsWe found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

AB - BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.MethodsIn this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.ResultsWe found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

KW - Affective Disorders

KW - Copy Number Variation

KW - Depression

KW - Genetics

KW - Phenotypes

U2 - 10.1016/j.biopsych.2015.02.025

DO - 10.1016/j.biopsych.2015.02.025

M3 - Article

SN - 0006-3223

JO - Biological Psychiatry

JF - Biological Psychiatry

ER -

Phenotypic association analyses with copy number variation in recurrent depressive disorder

Abstract

Keywords

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