title: Olanzapine-induced methylation alters cadherin gene families and associated pathways implicated in psychosis.
abstract: BACKGROUND
  The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders.
  
  
  RESULTS
  The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment.
  
  
  CONCLUSIONS
  The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis.
authors.forename: Melkaye G
authors.initials: MG
authors.lastname: Melka
authors.forename: Christina A
authors.initials: CA
authors.lastname: Castellani
authors.forename: Nagalingam
authors.initials: N
authors.lastname: Rajakumar
authors.forename: Richard
authors.initials: R
authors.lastname: O'Reilly
authors.affiliation: Molecular Genetics Unit, Department of Biology, The University of Western Ontario, London, ON N6A 5B7, Canada. ssingh@uwo.ca.
authors.forename: Shiva M
authors.initials: SM
authors.lastname: Singh
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077152:Olanzapine; D011401:Promoter Regions, Genetic; D011618:Psychotic Disorders / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D015820:Cadherins; D001569:Benzodiazepines; D000077152:Olanzapine