Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects

Mol Psychiatry. 2018 Mar;23(3):708-712. doi: 10.1038/mp.2017.111. Epub 2017 May 30.

Abstract

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antipsychotic Agents / therapeutic use
  • Brain / drug effects
  • Brain / metabolism
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Gene Expression Regulation / drug effects
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Genomics / methods
  • Haloperidol / metabolism*
  • Haloperidol / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Risk Factors
  • Schizophrenia / genetics*
  • Schizophrenic Psychology
  • Sequence Analysis, RNA

Substances

  • Antipsychotic Agents
  • Haloperidol