Genome-wide association study reveals two new risk loci for bipolar disorder

Thomas W. Mühleisen; Markus Leber; Thomas G. Schulze; Jana Strohmaier; Franziska Degenhardt; Jens Treutlein; Manuel Mattheisen; Andreas J. Forstner; Johannes Schumacher; René Breuer; Sandra Meier; Stefan Herms; Per Hoffmann; André Lacour; Stephanie H. Witt; Andreas Reif; Bertram Müller-Myhsok; Susanne Lucae; Wolfgang Maier; Markus Schwarz; Helmut Vedder; Jutta Kammerer-Ciernioch; Andrea Pfennig; Michael Bauer; Martin Hautzinger; Susanne Moebus; Lutz Priebe; Piotr M. Czerski; Joanna Hauser; Jolanta Lissowska; Neonila Szeszenia-Dabrowska; Paul Brennan; James D. McKay; Adam Wright; Philip B. Mitchell; Janice M. Fullerton; Peter R. Schofield; Grant W. Montgomery; Sarah E. Medland; Scott D. Gordon; Nicholas G. Martin; Valery Krasnow; Alexander Chuchalin; Gulja Babadjanova; Galina Pantelejeva; Lilia I. Abramova; Alexander S. Tiganov; Alexey Polonikov; Elza Khusnutdinova; Martin Alda; Paul Grof; Guy A. Rouleau; Gustavo Turecki; Catherine Laprise; Fabio Rivas; Fermin Mayoral; Manolis Kogevinas; Maria Grigoroiu-Serbanescu; Peter Propping; Tim Becker; Marcella Rietschel; Markus M. Nöthen; Sven Cichon

doi:10.1038/ncomms4339

Genome-wide association study reveals two new risk loci for bipolar disorder

Thomas W. Mühleisen, Markus Leber, Thomas G. Schulze, Jana Strohmaier, Franziska Degenhardt, Jens Treutlein, Manuel Mattheisen, Andreas J. Forstner, Johannes Schumacher, René Breuer, Sandra Meier, Stefan Herms, Per Hoffmann, André Lacour, Stephanie H. Witt, Andreas Reif, Bertram Müller-Myhsok, Susanne Lucae, Wolfgang Maier, Markus SchwarzHelmut Vedder, Jutta Kammerer-Ciernioch, Andrea Pfennig, Michael Bauer, Martin Hautzinger, Susanne Moebus, Lutz Priebe, Piotr M. Czerski, Joanna Hauser, Jolanta Lissowska, Neonila Szeszenia-Dabrowska, Paul Brennan, James D. McKay, Adam Wright, Philip B. Mitchell, Janice M. Fullerton, Peter R. Schofield, Grant W. Montgomery, Sarah E. Medland, Scott D. Gordon, Nicholas G. Martin, Valery Krasnow, Alexander Chuchalin, Gulja Babadjanova, Galina Pantelejeva, Lilia I. Abramova, Alexander S. Tiganov, Alexey Polonikov, Elza Khusnutdinova, Martin Alda, Paul Grof, Guy A. Rouleau, Gustavo Turecki, Catherine Laprise, Fabio Rivas, Fermin Mayoral, Manolis Kogevinas, Maria Grigoroiu-Serbanescu, Peter Propping, Tim Becker, Marcella Rietschel, Markus M. Nöthen, Sven Cichon

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Resumen

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

Idioma original	English
Número de artículo	3339
Publicación	Nature Communications
Volumen	5
DOI	https://doi.org/10.1038/ncomms4339
Estado	Published - mar. 11 2014
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
We are grateful to all patients and control subjects who contributed to this study. 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 M.M.N. and S.C., grant 01GS08147 to M.R.), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme. M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Canadian patients were genotyped within the ConLiGen project (www.ConLiGen.org), supported by a grant from the Deutsche Forschungsgemeinschaft to M.R., M.B., and T.G.S. (RI 908/7-1). Controls for Germany II were drawn from the Heinz Nixdorf Recall Study (HNR) cohort, which was established with the support of the Heinz Nixdorf Foundation. Recruitment of the Australian sample was supported by the Australian NHMRC program grant number 1037196. The collection of the Canadian patients has been supported by a grant from the Canadian Institutes of Health Research #64410 to M.A. Our study uses data generated by the GABRIEL consortium (controls for the sample Russia). Funding for these data was provided by the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control and the Wellcome Trust under award 084703. Canadian controls were drawn from the French Canadian study (SLSJ) that was partially supported by the Canada Research Chair, the Canadian Institutes of Health Research (Operating grant No. MOP-13506) and the Quebec Respiratory Network of the Fonds de recherche en Santé du Québec (FRQS). Polish controls were produced by the International Agency for Research on Cancer (IARC)/Centre National de Genotypage (CNG) GWAS Initiative. We thank the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium (PGC-BD) for providing access to the relevant data.

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

ODS de las Naciones Unidas

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Mühleisen, T. W., Leber, M., Schulze, T. G., Strohmaier, J., Degenhardt, F., Treutlein, J., Mattheisen, M., Forstner, A. J., Schumacher, J., Breuer, R., Meier, S., Herms, S., Hoffmann, P., Lacour, A., Witt, S. H., Reif, A., Müller-Myhsok, B., Lucae, S., Maier, W., ... Cichon, S. (2014). Genome-wide association study reveals two new risk loci for bipolar disorder. Nature Communications, 5, Artículo 3339. https://doi.org/10.1038/ncomms4339

Mühleisen, TW, Leber, M, Schulze, TG, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Forstner, AJ, Schumacher, J, Breuer, R, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Priebe, L, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnow, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Grof, P, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Propping, P, Becker, T, Rietschel, M, Nöthen, MM & Cichon, S 2014, 'Genome-wide association study reveals two new risk loci for bipolar disorder', Nature Communications, vol. 5, 3339. https://doi.org/10.1038/ncomms4339

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title = "Genome-wide association study reveals two new risk loci for bipolar disorder",

abstract = "Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.",

author = "M{\"u}hleisen, {Thomas W.} and Markus Leber and Schulze, {Thomas G.} and Jana Strohmaier and Franziska Degenhardt and Jens Treutlein and Manuel Mattheisen and Forstner, {Andreas J.} and Johannes Schumacher and Ren{\'e} Breuer and Sandra Meier and Stefan Herms and Per Hoffmann and Andr{\'e} Lacour and Witt, {Stephanie H.} and Andreas Reif and Bertram M{\"u}ller-Myhsok and Susanne Lucae and Wolfgang Maier and Markus Schwarz and Helmut Vedder and Jutta Kammerer-Ciernioch and Andrea Pfennig and Michael Bauer and Martin Hautzinger and Susanne Moebus and Lutz Priebe and Czerski, {Piotr M.} and Joanna Hauser and Jolanta Lissowska and Neonila Szeszenia-Dabrowska and Paul Brennan and McKay, {James D.} and Adam Wright and Mitchell, {Philip B.} and Fullerton, {Janice M.} and Schofield, {Peter R.} and Montgomery, {Grant W.} and Medland, {Sarah E.} and Gordon, {Scott D.} and Martin, {Nicholas G.} and Valery Krasnow and Alexander Chuchalin and Gulja Babadjanova and Galina Pantelejeva and Abramova, {Lilia I.} and Tiganov, {Alexander S.} and Alexey Polonikov and Elza Khusnutdinova and Martin Alda and Paul Grof and Rouleau, {Guy A.} and Gustavo Turecki and Catherine Laprise and Fabio Rivas and Fermin Mayoral and Manolis Kogevinas and Maria Grigoroiu-Serbanescu and Peter Propping and Tim Becker and Marcella Rietschel and N{\"o}then, {Markus M.} and Sven Cichon",

note = "Funding Information: We are grateful to all patients and control subjects who contributed to this study. 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 M.M.N. and S.C., grant 01GS08147 to M.R.), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme. M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Canadian patients were genotyped within the ConLiGen project (www.ConLiGen.org), supported by a grant from the Deutsche Forschungsgemeinschaft to M.R., M.B., and T.G.S. (RI 908/7-1). Controls for Germany II were drawn from the Heinz Nixdorf Recall Study (HNR) cohort, which was established with the support of the Heinz Nixdorf Foundation. Recruitment of the Australian sample was supported by the Australian NHMRC program grant number 1037196. The collection of the Canadian patients has been supported by a grant from the Canadian Institutes of Health Research #64410 to M.A. Our study uses data generated by the GABRIEL consortium (controls for the sample Russia). Funding for these data was provided by the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control and the Wellcome Trust under award 084703. Canadian controls were drawn from the French Canadian study (SLSJ) that was partially supported by the Canada Research Chair, the Canadian Institutes of Health Research (Operating grant No. MOP-13506) and the Quebec Respiratory Network of the Fonds de recherche en Sant{\'e} du Qu{\'e}bec (FRQS). Polish controls were produced by the International Agency for Research on Cancer (IARC)/Centre National de Genotypage (CNG) GWAS Initiative. We thank the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium (PGC-BD) for providing access to the relevant data.",

year = "2014",

month = mar,

day = "11",

doi = "10.1038/ncomms4339",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Genome-wide association study reveals two new risk loci for bipolar disorder

AU - Mühleisen, Thomas W.

AU - Leber, Markus

AU - Schulze, Thomas G.

AU - Strohmaier, Jana

AU - Degenhardt, Franziska

AU - Treutlein, Jens

AU - Mattheisen, Manuel

AU - Forstner, Andreas J.

AU - Schumacher, Johannes

AU - Breuer, René

AU - Meier, Sandra

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Lacour, André

AU - Witt, Stephanie H.

AU - Reif, Andreas

AU - Müller-Myhsok, Bertram

AU - Lucae, Susanne

AU - Maier, Wolfgang

AU - Schwarz, Markus

AU - Vedder, Helmut

AU - Kammerer-Ciernioch, Jutta

AU - Pfennig, Andrea

AU - Bauer, Michael

AU - Hautzinger, Martin

AU - Moebus, Susanne

AU - Priebe, Lutz

AU - Czerski, Piotr M.

AU - Hauser, Joanna

AU - Lissowska, Jolanta

AU - Szeszenia-Dabrowska, Neonila

AU - Brennan, Paul

AU - McKay, James D.

AU - Wright, Adam

AU - Mitchell, Philip B.

AU - Fullerton, Janice M.

AU - Schofield, Peter R.

AU - Montgomery, Grant W.

AU - Medland, Sarah E.

AU - Gordon, Scott D.

AU - Martin, Nicholas G.

AU - Krasnow, Valery

AU - Chuchalin, Alexander

AU - Babadjanova, Gulja

AU - Pantelejeva, Galina

AU - Abramova, Lilia I.

AU - Tiganov, Alexander S.

AU - Polonikov, Alexey

AU - Khusnutdinova, Elza

AU - Alda, Martin

AU - Grof, Paul

AU - Rouleau, Guy A.

AU - Turecki, Gustavo

AU - Laprise, Catherine

AU - Rivas, Fabio

AU - Mayoral, Fermin

AU - Kogevinas, Manolis

AU - Grigoroiu-Serbanescu, Maria

AU - Propping, Peter

AU - Becker, Tim

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Cichon, Sven

N1 - Funding Information: We are grateful to all patients and control subjects who contributed to this study. 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 M.M.N. and S.C., grant 01GS08147 to M.R.), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme. M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Canadian patients were genotyped within the ConLiGen project (www.ConLiGen.org), supported by a grant from the Deutsche Forschungsgemeinschaft to M.R., M.B., and T.G.S. (RI 908/7-1). Controls for Germany II were drawn from the Heinz Nixdorf Recall Study (HNR) cohort, which was established with the support of the Heinz Nixdorf Foundation. Recruitment of the Australian sample was supported by the Australian NHMRC program grant number 1037196. The collection of the Canadian patients has been supported by a grant from the Canadian Institutes of Health Research #64410 to M.A. Our study uses data generated by the GABRIEL consortium (controls for the sample Russia). Funding for these data was provided by the European Commission as part of GABRIEL contract number 018996 under the Integrated Program LSH-2004-1.2.5-1. Post genomic approaches to understand the molecular basis of asthma aiming at a preventive or therapeutic control and the Wellcome Trust under award 084703. Canadian controls were drawn from the French Canadian study (SLSJ) that was partially supported by the Canada Research Chair, the Canadian Institutes of Health Research (Operating grant No. MOP-13506) and the Quebec Respiratory Network of the Fonds de recherche en Santé du Québec (FRQS). Polish controls were produced by the International Agency for Research on Cancer (IARC)/Centre National de Genotypage (CNG) GWAS Initiative. We thank the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium (PGC-BD) for providing access to the relevant data.

PY - 2014/3/11

Y1 - 2014/3/11

N2 - Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

AB - Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

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U2 - 10.1038/ncomms4339

DO - 10.1038/ncomms4339

M3 - Article

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VL - 5

JO - Nature Communications

JF - Nature Communications

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ER -

Genome-wide association study reveals two new risk loci for bipolar disorder

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

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