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J Affect Disord. 2018 Mar 1;228:20-25. doi: 10.1016/j.jad.2017.11.068. Epub 2017 Nov 14.

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

Author information

1
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.
2
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.
3
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.
4
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
5
Department of Psychiatry, Dalhousie University, Halifax, Canada; National Institute of Mental Health, Klecany, Czech Republic.
6
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
7
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
8
Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
9
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.
10
Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
11
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences Faculty of Medicine, University of New South Wales, Sydney, Australia.
12
Queensland Institute of Medical Research (QIMR), Brisbane, Australia.
13
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
14
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.
15
Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
16
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.
17
Center of Psychiatry Weinsberg, Weinsberg, Germany.
18
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.
19
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
20
Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
21
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
22
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.
23
Department of Psychiatry & Psychotherapy, University of Cologne, Cologne, Germany.
24
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
25
Max Planck Institute of Psychiatry, Munich, Germany.
26
Department of Psychiatry, University of Bonn, Bonn, Germany.
27
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.
28
Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
29
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer (IARC), Lyon, France.
30
School of Psychiatry, University of New South Wales, Randwick, Australia; Black Dog Institute, Prince of Wales Hospital, Randwick, Australia.
31
Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
32
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.
33
Psychiatric Clinic, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina.
34
Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Zmaja od Bosne 8 - Campus, 71000 Sarajevo, Bosnia and Herzegovina.
35
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.
36
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
37
Montreal Neurological Institute, McGill University, Montreal, Canada.
38
Psychiatric Center Nordbaden, Wiesloch, Germany.
39
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
40
Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
41
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.
42
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
43
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.

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:

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.

KEYWORDS:

Bipolar disorder; GRB2 events in ERBB2 signaling; NCAM signaling for neurite out-growth; Neurodevelopmental disorder; Pathway analysis

PMID:
29197740
DOI:
10.1016/j.jad.2017.11.068
[Indexed for MEDLINE]

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