title: Risk architecture of schizophrenia:  the role of epigenetics.
abstract: OBJECTIVE
  To systematize existing data and review new findings on the cause of schizophrenia and outline an improved mixed model of schizophrenia risk.
  
  
  RESULTS
  Multiple and variable genetic and environmental factors interact to influence the risk of schizophrenia. Both rare variants with large effect and common variants with small effect contribute to genetic risk of schizophrenia, with no indication for differential impact on its clinical features. Accumulating evidence supports a genetic architecture of schizophrenia with multiple scenarios, including additive polygenic, heterogeneity, and mixed polygenic-heterogeneity. The epigenetic mechanisms that mediate gene-environment (GxE) interactions provide a framework to incorporate environmental factors into models of schizophrenia risk. Environmental pathogens with small effect on risk have robust effects in the context of family history of schizophrenia. Hence, genetic risk for schizophrenia may be expressed in part as sensitivity to environmental factors.
  
  
  CONCLUSIONS
  We propose an improved mixed model of schizophrenia risk in which abnormal epigenetic states with large effects are superimposed on a polygenic liability to schizophrenia. This scenario can account for GxE interactions and shared family environment, which in many cases are not explained by a single structural variant of large effect superimposed on polygenes (the traditional mixed model).
authors: Department of Psychiatry, Washington University School of Medicine in St Louis, 660 S Euclid Avenue, Campus Box 8134, St Louis, MO 63110, USA. svrakicd@psychiatry.wustl.edu
authors: Dragan M
authors: DM
authors: Svrakic
authors: Charles F
authors: CF
authors: Zorumski
authors: Nenad M
authors: NM
authors: Svrakic
authors: Igor
authors: I
authors: Zwir
authors: Claude R
authors: CR
authors: Cloninger
mesh_terms: D044127:Epigenesis, Genetic; D059647:Gene-Environment Interaction; D006801:Humans; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*