Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
29197740
TITLE
Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.
ABSTRACT
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
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. 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
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. 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. 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
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. 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. 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. 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
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. 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. 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. 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. 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.
Copyright © 2017 Elsevier B.V. All rights reserved.
DATE PUBLISHED
2018 03 01
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2017/07/20
revised 2017/10/20
accepted 2017/11/12
pubmed 2017/12/05 06:00
medline 2018/09/05 06:00
entrez 2017/12/04 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Mühleisen TW Mühleisen Thomas W TW 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.
Reinbold CS Reinbold Céline S CS 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.
Forstner AJ Forstner Andreas J AJ 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.
Abramova LI Abramova Lilia I LI Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Alda M Alda Martin M Department of Psychiatry, Dalhousie University, Halifax, Canada; National Institute of Mental Health, Klecany, Czech Republic.
Babadjanova G Babadjanova Gulja G Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
Bauer M Bauer Michael M Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
Brennan P Brennan Paul P Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
Chuchalin A Chuchalin Alexander A Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
Cruceanu C Cruceanu Cristiana C Montreal Neurological Institute, McGill University, Montreal, Canada; Department of Human Genetics, McGill University, Montreal, Canada; McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada.
Czerski PM Czerski Piotr M PM Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Degenhardt F Degenhardt Franziska F 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.
Fischer SB Fischer Sascha B SB 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.
Fullerton JM Fullerton Janice M JM Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
Gordon SD Gordon Scott D SD Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Grigoroiu-Serbanescu M Grigoroiu-Serbanescu Maria M Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
Grof P Grof Paul P 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.
Hauser J Hauser Joanna J Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Hautzinger M Hautzinger Martin M Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
Herms S Herms Stefan S 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.
Hoffmann P Hoffmann Per P 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.
Kammerer-Ciernioch J Kammerer-Ciernioch Jutta J Center of Psychiatry Weinsberg, Weinsberg, Germany.
Khusnutdinova E Khusnutdinova Elza E 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.
Kogevinas M Kogevinas Manolis M Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
Krasnov V Krasnov Valery V Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
Lacour A Lacour André A German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Laprise C Laprise Catherine C Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, QC, Canada; Centre intégré universitaire de santé et services sociaux du Saguenay-Lac-Saint-Jean, Saguenay, Québec, Canada.
Leber M Leber Markus M Department of Psychiatry & Psychotherapy, University of Cologne, Cologne, Germany.
Lissowska J Lissowska Jolanta J Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
Lucae S Lucae Susanne S Max Planck Institute of Psychiatry, Munich, Germany.
Maaser A Maaser Anna A 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.
Maier W Maier Wolfgang W Department of Psychiatry, University of Bonn, Bonn, Germany.
Martin NG Martin Nicholas G NG Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Mattheisen M Mattheisen Manuel M Department of Biomedicine and Centre for integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
Mayoral F Mayoral Fermin F Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
McKay JD McKay James D JD Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
Medland SE Medland Sarah E SE Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Mitchell PB Mitchell Philip B PB School of Psychiatry, University of New South Wales, Randwick, Australia; Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
Moebus S Moebus Susanne S Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
Montgomery GW Montgomery Grant W GW Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
Müller-Myhsok B Müller-Myhsok Bertram B Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; University of Liverpool, Institute of Translational Medicine, Liverpool, United Kingdom.
Oruc L Oruc Lilijana L Psychiatric Clinic, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina.
Pantelejeva G Pantelejeva Galina G Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Pfennig A Pfennig Andrea A Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
Pojskic L Pojskic Lejla L Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Zmaja od Bosne 8 - Campus, 71000 Sarajevo, Bosnia and Herzegovina.
Polonikov A Polonikov Alexey A Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation; Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk, Russian Federation.
Reif A Reif Andreas A Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
Rivas F Rivas Fabio F Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
Rouleau GA Rouleau Guy A GA Montreal Neurological Institute, McGill University, Montreal, Canada.
Schenk LM Schenk Lorena M LM 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.
Schofield PR Schofield Peter R PR Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
Schwarz M Schwarz Markus M Psychiatric Center Nordbaden, Wiesloch, Germany.
Streit F Streit Fabian F Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Strohmaier J Strohmaier Jana J Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Szeszenia-Dabrowska N Szeszenia-Dabrowska Neonila N Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
Tiganov AS Tiganov Alexander S AS Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Treutlein J Treutlein Jens J Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Turecki G Turecki Gustavo G Department of Human Genetics, McGill University, Montreal, Canada; McGill Group for Suicide Studies & Douglas Research Institute, Montreal, Canada; Department of Psychiatry, McGill University, Montreal, Canada.
Vedder H Vedder Helmut H Psychiatric Center Nordbaden, Wiesloch, Germany.
Witt SH Witt Stephanie H SH Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Schulze TG Schulze Thomas G TG Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
Rietschel M Rietschel Marcella M Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Nöthen MM Nöthen Markus M MM 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.
Cichon S Cichon Sven S 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; 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. Electronic address: sven.cichon@unibas.ch.
INVESTIGATORS
JOURNAL
VOLUME: 228
ISSUE:
TITLE: Journal of affective disorders
ISOABBREVIATION: J Affect Disord
YEAR: 2018
MONTH: 03
DAY: 01
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1573-2517
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: J Affect Disord
COUNTRY: Netherlands
ISSNLINKING: 0165-0327
NLMUNIQUEID: 7906073
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
MOP-13506 Canadian Institutes of Health Research International
GENERAL NOTE
KEYWORDS
KEYWORD
Bipolar disorder
GRB2 events in ERBB2 signaling
NCAM signaling for neurite out-growth
Neurodevelopmental disorder
Pathway analysis
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Algorithms
Bipolar Disorder physiopathology
Brain metabolism
Female metabolism
GRB2 Adaptor Protein metabolism
Gene Expression metabolism
Genes, erbB-2 physiology
Genetic Predisposition to Disease physiology
Genome-Wide Association Study physiology
Humans physiology
Male physiology
Phenotype physiology
Polymorphism, Single Nucleotide physiology
RNA metabolism
Receptor, ErbB-2 metabolism
Signal Transduction metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 GRB2 Adaptor Protein
0 GRB2 protein, human
63231-63-0 RNA
EC 2.7.10.1 Receptor, ErbB-2
OTHER ID's
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