title: Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.
abstract: In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dilafruz
authors.initials: D
authors.lastname: Juraeva
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany; Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Haenisch
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Josef
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: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; Institute for Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Jens
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: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; National Centre for Integrated Register-based Research (NCRR), Department of Economics and Business, Aarhus University, Aarhus, Denmark.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany; Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Leber
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Genomic Mathematics, University of Bonn, Bonn, Germany; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Göttingen, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.affiliation: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Nenadic
authors.affiliation: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sauer
authors.affiliation: Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany; Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark and Center for Integrated Sequencing, iSEQ, Aarhus, Denmark; Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Børglum
authors.affiliation: UCLA Center for Neurobehavioral Genetics, Los Angeles, California, United States of America; Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Ophoff
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; Institute for Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany; Department of Medical Genetics, University Hospital Basel, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; Department of Genomic Mathematics, University of Bonn, Bonn, Germany; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Biomedicine, Aarhus University, Aarhus C, Denmark and Center for Integrated Sequencing, iSEQ, Aarhus, Denmark; Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D020746:Calcium Channels, L-Type / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D026901:Membrane Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
chemical_list: C107597:CACNB2 protein, human; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D020746:Calcium Channels, L-Type; D002843:Chromatin; D026901:Membrane Transport Proteins; D012097:Repressor Proteins; C477339:ARL5B protein, human; D020727:ADP-Ribosylation Factors