PLoS Genetics (Jun 2014)

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

  • Dilafruz Juraeva,
  • Britta Haenisch,
  • Marc Zapatka,
  • Josef Frank,
  • GROUP Investigators,
  • PSYCH-GEMS SCZ Working Group,
  • Stephanie H Witt,
  • Thomas W Mühleisen,
  • Jens Treutlein,
  • Jana Strohmaier,
  • Sandra Meier,
  • Franziska Degenhardt,
  • Ina Giegling,
  • Stephan Ripke,
  • Markus Leber,
  • Christoph Lange,
  • Thomas G Schulze,
  • Rainald Mössner,
  • Igor Nenadic,
  • Heinrich Sauer,
  • Dan Rujescu,
  • Wolfgang Maier,
  • Anders Børglum,
  • Roel Ophoff,
  • Sven Cichon,
  • Markus M Nöthen,
  • Marcella Rietschel,
  • Manuel Mattheisen,
  • Benedikt Brors

DOI
https://doi.org/10.1371/journal.pgen.1004345
Journal volume & issue
Vol. 10, no. 6
p. e1004345

Abstract

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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.