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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • CCCTC-Binding Factor
  • Calcium Channels, L-Type / genetics*
  • Calcium Signaling / genetics
  • Chromatin / metabolism
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Membrane Transport Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Repressor Proteins / genetics*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism

Substances

  • CACNB2 protein, human
  • CCCTC-Binding Factor
  • CTCF protein, human
  • Calcium Channels, L-Type
  • Chromatin
  • Membrane Transport Proteins
  • Repressor Proteins
  • ARL5B protein, human
  • ADP-Ribosylation Factors

Grant support

This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to MMN and SC, grant 01GS08147 to MR, grant 01GS08149 to BB), under the auspices of the National Genome Research Network plus (NGFNplus). The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 279227 (CRESTAR). Further funding came from the European Union Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 242257 (ADAMS). The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation (Dr G Schmidt, Chairman). MMN is a member of the DFG-funded Excellence Cluster ImmunoSensation. IN was supported by a Junior Scientist Grant (Rotationsstelle) of IZKF, Jena University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.