title: Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.
abstract: Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: S H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Juraeva
authors.affiliation: Medical Research Center, University Hospital Mannheim, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: National Center for Register-based Research, Aarhus University, Aarhus C, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Meier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Dukal
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lang
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Deuschle
authors.affiliation: Section of Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Centre Göttingen, Göttingen, Germany.
authors.forename: T G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: 1] Department of Biomedicine, Aarhus University, Aarhus C, Denmark [2] Department of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Medical Genetics, University Hospital Basel, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Cichon
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn, Germany [2] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Anaesthesiology and Operative Intensive Care, University Hospital Mannheim, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: C C
authors.initials: CC
authors.lastname: Witt
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D016201:Receptors, Lymphocyte Homing / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D005819:Genetic Markers; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human