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PLoS Genet. 2014 Jun 5;10(6):e1004345. doi: 10.1371/journal.pgen.1004345. eCollection 2014 Jun.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

Author information

1
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
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.
3
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
5
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.
6
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.
7
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
8
Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany; Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
9
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.
10
Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
11
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.
12
Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Göttingen, Germany.
13
Department of Psychiatry, University of Bonn, Bonn, Germany.
14
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
15
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.
16
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.
17
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.
18
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.

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.

PMID:
24901509
PMCID:
PMC4046913
DOI:
10.1371/journal.pgen.1004345
[Indexed for MEDLINE]
Free PMC Article

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