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

^*Corresponding author for this work

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

18 Citations (Scopus)

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
Volume	79
Issue	4
Pages (from-to)	329-336
Number of pages	8
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2015.02.025
Publication status	Published - 15 Feb 2016

Keywords

Affective disorders
Copy number variation
Depression
Genetics
Phenotypes
SEX-CHROMOSOME ABNORMALITIES
HIDDEN-MARKOV MODEL
SNP GENOTYPING DATA
UNIPARENTAL DISOMY
BIPOLAR DISORDER
MAJOR DEPRESSION
SCHIZOPHRENIA
VARIANTS
MOSAICISM
DUPLICATIONS

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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. (2016). Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder. Biological Psychiatry, 79(4), 329-336. https://doi.org/10.1016/j.biopsych.2015.02.025

@article{c8863ce59e7b46dbbc21346918309d88,

title = "Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder",

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.",

keywords = "Affective disorders, Copy number variation, Depression, Genetics, Phenotypes, SEX-CHROMOSOME ABNORMALITIES, HIDDEN-MARKOV MODEL, SNP GENOTYPING DATA, UNIPARENTAL DISOMY, BIPOLAR DISORDER, MAJOR DEPRESSION, SCHIZOPHRENIA, VARIANTS, MOSAICISM, DUPLICATIONS",

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 = "2016",

month = feb,

day = "15",

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

language = "English",

volume = "79",

pages = "329--336",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "4",

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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 2016, 'Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder', Biological Psychiatry, vol. 79, no. 4, pp. 329-336. https://doi.org/10.1016/j.biopsych.2015.02.025

Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder. / Rucker, James J. H.; Tansey, Katherine E.; Rivera, Margarita et al.
In: Biological Psychiatry, Vol. 79, No. 4, 15.02.2016, p. 329-336.

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

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 - 2016/2/15

Y1 - 2016/2/15

N2 - 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.

AB - 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.

KW - Affective disorders

KW - Copy number variation

KW - Depression

KW - Genetics

KW - Phenotypes

KW - SEX-CHROMOSOME ABNORMALITIES

KW - HIDDEN-MARKOV MODEL

KW - SNP GENOTYPING DATA

KW - UNIPARENTAL DISOMY

KW - BIPOLAR DISORDER

KW - MAJOR DEPRESSION

KW - SCHIZOPHRENIA

KW - VARIANTS

KW - MOSAICISM

KW - DUPLICATIONS

UR - http://www.scopus.com/inward/record.url?scp=84955180285&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2015.02.025

DO - 10.1016/j.biopsych.2015.02.025

M3 - Journal article

C2 - 25861698

SN - 0006-3223

VL - 79

SP - 329

EP - 336

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 4

ER -

Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder

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