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Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder
TW. Mühleisen, CS. Reinbold, AJ. Forstner, LI. Abramova, M. Alda, G. Babadjanova, M. Bauer, P. Brennan, A. Chuchalin, C. Cruceanu, PM. Czerski, F. Degenhardt, SB. Fischer, JM. Fullerton, SD. Gordon, M. Grigoroiu-Serbanescu, P. Grof, J. Hauser, M....
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- adaptorový protein GRB2 genetika metabolismus MeSH
- algoritmy MeSH
- bipolární porucha genetika metabolismus patofyziologie MeSH
- celogenomová asociační studie MeSH
- exprese genu MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- geny erbB-2 fyziologie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mozek růst a vývoj metabolismus MeSH
- receptor erbB-2 metabolismus MeSH
- RNA metabolismus MeSH
- signální transdukce * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.
Black Dog Institute Prince of Wales Hospital Randwick Australia
Center for Research in Environmental Epidemiology Barcelona Spain
Center of Psychiatry Weinsberg Weinsberg Germany
Département des sciences fondamentales Université du Québec à Chicoutimi Saguenay QC Canada
Department of Epidemiology Nofer Institute of Occupational Medicine Lodz Poland
Department of Genetics and Fundamental Medicine of Bashkir State University Ufa Russian Federation
Department of Genomics Life and Brain Research Center University of Bonn Bonn Germany
Department of Human Genetics McGill University Montreal Canada
Department of Psychiatry and Psychotherapy University of Cologne Cologne Germany
Department of Psychiatry Dalhousie University Halifax Canada
Department of Psychiatry Hospital Regional Universitario Biomedical Institute of Malaga Malaga Spain
Department of Psychiatry McGill University Montreal Canada
Department of Psychiatry University of Bonn Bonn Germany
Department of Psychiatry University of Toronto Toronto Ontario Canada M5T 1R8
Genetic Cancer Susceptibility Group International Agency for Research on Cancer Lyon France
Genetic Epidemiology Group International Agency for Research on Cancer Lyon France
German Center for Neurodegenerative Diseases Bonn Germany
Institute of Medical Informatics Biometry and Epidemiology University Duisburg Essen Essen Germany
Institute of Neuroscience and Medicine Research Centre Jülich Jülich Germany
Institute of Psychiatric Phenomics and Genomics Ludwig Maximilians University Munich Munich Germany
Institute of Pulmonology Russian State Medical University Moscow Russian Federation
Max Planck Institute of Psychiatry Munich Germany
McGill Group for Suicide Studies and Douglas Research Institute Montreal Canada
Montreal Neurological Institute McGill University Montreal Canada
Mood Disorders Center of Ottawa Ottawa Ontario Canada K1G 4G3
Moscow Research Institute of Psychiatry Moscow Russian Federation
Munich Cluster for Systems Neurology Munich Germany
National Institute of Mental Health Klecany Czech Republic
Neuroscience Research Australia Sydney Australia
Psychiatric Center Nordbaden Wiesloch Germany
Queensland Institute of Medical Research Brisbane Australia
Russian Academy of Medical Sciences Mental Health Research Center Moscow Russian Federation
School of Medical Sciences Faculty of Medicine University of New South Wales Sydney Australia
School of Psychiatry University of New South Wales Randwick Australia
The International Group for the Study of Lithium Treated Patients Berlin Germany
University of Liverpool Institute of Translational Medicine Liverpool United Kingdom
Citace poskytuje Crossref.org
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- $a Mühleisen, Thomas W $u Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; Department of Biomedicine & Institute of Medical Genetics and Pathology, Human Genomics Research Group and Division of Medical Genetics, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
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- $a Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder / $c TW. Mühleisen, CS. Reinbold, AJ. Forstner, LI. Abramova, M. Alda, G. Babadjanova, M. Bauer, P. Brennan, A. Chuchalin, C. Cruceanu, PM. Czerski, F. Degenhardt, SB. Fischer, JM. Fullerton, SD. Gordon, M. Grigoroiu-Serbanescu, P. Grof, J. Hauser, M. Hautzinger, S. Herms, P. Hoffmann, J. Kammerer-Ciernioch, E. Khusnutdinova, M. Kogevinas, V. Krasnov, A. Lacour, C. Laprise, M. Leber, J. Lissowska, S. Lucae, A. Maaser, W. Maier, NG. Martin, M. Mattheisen, F. Mayoral, JD. McKay, SE. Medland, PB. Mitchell, S. Moebus, GW. Montgomery, B. Müller-Myhsok, L. Oruc, G. Pantelejeva, A. Pfennig, L. Pojskic, A. Polonikov, A. Reif, F. Rivas, GA. Rouleau, LM. Schenk, PR. Schofield, M. Schwarz, F. Streit, J. Strohmaier, N. Szeszenia-Dabrowska, AS. Tiganov, J. Treutlein, G. Turecki, H. Vedder, SH. Witt, TG. Schulze, M. Rietschel, MM. Nöthen, S. Cichon,
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- $a BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.
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- $a Reinbold, Céline S $u Department of Biomedicine & Institute of Medical Genetics and Pathology, Human Genomics Research Group and Division of Medical Genetics, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
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- $a Forstner, Andreas J $u Institute of Human Genetics, Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany.
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- $a Abramova, Lilia I $u Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
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- 700 1_
- $a Babadjanova, Gulja $u Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
- 700 1_
- $a Bauer, Michael $u Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
- 700 1_
- $a Brennan, Paul $u Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
- 700 1_
- $a Chuchalin, Alexander $u Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
- 700 1_
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- 700 1_
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- 700 1_
- $a Degenhardt, Franziska $u Institute of Human Genetics, Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany.
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- 700 1_
- $a Fullerton, Janice M $u Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
- 700 1_
- $a Gordon, Scott D $u Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
- 700 1_
- $a Grigoroiu-Serbanescu, Maria $u Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
- 700 1_
- $a Grof, Paul $u The International Group for the Study of Lithium-Treated Patients (IGSLI), Berlin, Germany; Mood Disorders Center of Ottawa, Ottawa, Ontario, Canada K1G 4G3; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5T 1R8.
- 700 1_
- $a Hauser, Joanna $u Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
- 700 1_
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- 700 1_
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- 700 1_
- $a Hoffmann, Per $u Department of Biomedicine & Institute of Medical Genetics and Pathology, Human Genomics Research Group and Division of Medical Genetics, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland; Institute of Human Genetics, Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany.
- 700 1_
- $a Kammerer-Ciernioch, Jutta $u Center of Psychiatry Weinsberg, Weinsberg, Germany.
- 700 1_
- $a Khusnutdinova, Elza $u Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russian Federation; Department of Genetics and Fundamental Medicine of Bashkir State University, Ufa, Russian Federation.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a McKay, James D $u Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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