Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

GROUP Consortium; Wellcome Trust Case Control Consortium 2; International Schizophrenia Consortium

doi:10.1038/tp.2013.101

Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

GROUP Consortium, Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium

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10 Citas (Scopus)

Resumen

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ∼80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10^-5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.

Idioma original	English
Número de artículo	tp2013101
Publicación	Translational Psychiatry
Volumen	3
DOI	https://doi.org/10.1038/tp.2013.101
Estado	Published - nov. 26 2013
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
We thank all of the patients for participating in this study. We are grateful to Professor H-E Wichmann for supplying the SNP-chip data from the KORA control cohort and Professor S Schreiber for providing access to the SNP-chip data from the PopGen control cohort. We thank all of the probands from the Heinz Nixdorf Recall (HNR) study and the MooDS Imaging controls. This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and by email from decipher@sanger.ac.uk. Funding for the project DECIPHER was provided by the Wellcome Trust. This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to MMN, SC and HW, grant 01GS08147 to MR, under the auspices of the National Genome Research Network plus (NGFNplus). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. MR was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257; CRESTAR project, HEALTH-2011-1.1-2) grant 279227. IN was supported by IZKF Jena (Junior Scientist Grant). In 2007 and 2008, Heinrich Sauer received fees for board membership by Lilly and Otsuka, a travel grant by Lilly and speaker's honoraria by Pfizer and Lilly, moreover, fees for a consultancy of Wyeth. The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation. The WTCCC2 schizophrenia analysis was funded by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B). We acknowledge use of the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls funded by the Wellcome Trust. These funding sources had no involvement in the study design, the collection, analysis and interpretation of data, the writing of the report or the decision to submit the paper for publication. We thank deCODE for sharing frequencies of the RB1CC1 duplications in their large genotyped sample of cases and controls.

Publisher Copyright:
© 2013 Macmillan Publishers Limited.

ASJC Scopus Subject Areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

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@article{5199b0a3c50344b2a225bcc773454c76,

title = "Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets",

abstract = "Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ∼80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10-5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.",

author = "{GROUP Consortium} and {Wellcome Trust Case Control Consortium 2} and {International Schizophrenia Consortium} and F. Degenhardt and L. Priebe and S. Meier and L. Lennertz and F. Streit and Witt, {S. H.} and A. Hofmann and T. Becker and R. M{\"o}ssner and W. Maier and I. Nenadic and H. Sauer and M. Mattheisen and J. Buizer-Voskamp and Ophoff, {R. A.} and D. Rujescu and I. Giegling and A. Ingason and M. Wagner and B. Delobel and J. Andrieux and A. Meyer-Lindenberg and A. Heinz and H. Walter and S. Moebus and A. Corvin and M. Rietschel and N{\"o}then, {M. M.} and S. Cichon and Kahn, {Ren{\'e} S.} and Linszen, {Don H.} and {Van Os}, Jim and Durk Wiersma and Richard Bruggeman and Wiepke Cahn and {De Haan}, Lieuwe and Lydia Krabbendam and Inez Myin-Germeys",

note = "Funding Information: We thank all of the patients for participating in this study. We are grateful to Professor H-E Wichmann for supplying the SNP-chip data from the KORA control cohort and Professor S Schreiber for providing access to the SNP-chip data from the PopGen control cohort. We thank all of the probands from the Heinz Nixdorf Recall (HNR) study and the MooDS Imaging controls. This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and by email from decipher@sanger.ac.uk. Funding for the project DECIPHER was provided by the Wellcome Trust. This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to MMN, SC and HW, grant 01GS08147 to MR, under the auspices of the National Genome Research Network plus (NGFNplus). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. MR was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257; CRESTAR project, HEALTH-2011-1.1-2) grant 279227. IN was supported by IZKF Jena (Junior Scientist Grant). In 2007 and 2008, Heinrich Sauer received fees for board membership by Lilly and Otsuka, a travel grant by Lilly and speaker's honoraria by Pfizer and Lilly, moreover, fees for a consultancy of Wyeth. The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation. The WTCCC2 schizophrenia analysis was funded by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B). We acknowledge use of the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls funded by the Wellcome Trust. These funding sources had no involvement in the study design, the collection, analysis and interpretation of data, the writing of the report or the decision to submit the paper for publication. We thank deCODE for sharing frequencies of the RB1CC1 duplications in their large genotyped sample of cases and controls. Publisher Copyright: {\textcopyright} 2013 Macmillan Publishers Limited.",

year = "2013",

month = nov,

day = "26",

doi = "10.1038/tp.2013.101",

language = "English",

volume = "3",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

AU - GROUP Consortium

AU - Wellcome Trust Case Control Consortium 2

AU - International Schizophrenia Consortium

AU - Degenhardt, F.

AU - Priebe, L.

AU - Meier, S.

AU - Lennertz, L.

AU - Streit, F.

AU - Witt, S. H.

AU - Hofmann, A.

AU - Becker, T.

AU - Mössner, R.

AU - Maier, W.

AU - Nenadic, I.

AU - Sauer, H.

AU - Mattheisen, M.

AU - Buizer-Voskamp, J.

AU - Ophoff, R. A.

AU - Rujescu, D.

AU - Giegling, I.

AU - Ingason, A.

AU - Wagner, M.

AU - Delobel, B.

AU - Andrieux, J.

AU - Meyer-Lindenberg, A.

AU - Heinz, A.

AU - Walter, H.

AU - Moebus, S.

AU - Corvin, A.

AU - Rietschel, M.

AU - Nöthen, M. M.

AU - Cichon, S.

AU - Kahn, René S.

AU - Linszen, Don H.

AU - Van Os, Jim

AU - Wiersma, Durk

AU - Bruggeman, Richard

AU - Cahn, Wiepke

AU - De Haan, Lieuwe

AU - Krabbendam, Lydia

AU - Myin-Germeys, Inez

N1 - Funding Information: We thank all of the patients for participating in this study. We are grateful to Professor H-E Wichmann for supplying the SNP-chip data from the KORA control cohort and Professor S Schreiber for providing access to the SNP-chip data from the PopGen control cohort. We thank all of the probands from the Heinz Nixdorf Recall (HNR) study and the MooDS Imaging controls. This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and by email from decipher@sanger.ac.uk. Funding for the project DECIPHER was provided by the Wellcome Trust. This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to MMN, SC and HW, grant 01GS08147 to MR, under the auspices of the National Genome Research Network plus (NGFNplus). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. MR was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257; CRESTAR project, HEALTH-2011-1.1-2) grant 279227. IN was supported by IZKF Jena (Junior Scientist Grant). In 2007 and 2008, Heinrich Sauer received fees for board membership by Lilly and Otsuka, a travel grant by Lilly and speaker's honoraria by Pfizer and Lilly, moreover, fees for a consultancy of Wyeth. The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation. The WTCCC2 schizophrenia analysis was funded by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B). We acknowledge use of the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls funded by the Wellcome Trust. These funding sources had no involvement in the study design, the collection, analysis and interpretation of data, the writing of the report or the decision to submit the paper for publication. We thank deCODE for sharing frequencies of the RB1CC1 duplications in their large genotyped sample of cases and controls. Publisher Copyright: © 2013 Macmillan Publishers Limited.

PY - 2013/11/26

Y1 - 2013/11/26

N2 - Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ∼80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10-5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.

AB - Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ∼80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10-5; odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.

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U2 - 10.1038/tp.2013.101

DO - 10.1038/tp.2013.101

M3 - Article

C2 - 26151896

AN - SCOPUS:84936864434

SN - 2158-3188

VL - 3

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - tp2013101

ER -

Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

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