Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development

Clin Genet. 2004 Jun;65(6):435-40. doi: 10.1111/j.1399-0004.2004.00269.x.

Abstract

Epidemiological data favors genetic predisposition for schizophrenia, a common and complex mental disorder in most populations. Search for the genes involved using candidate genes, positional cloning, and chromosomal aberrations including triplet repeat expansions have established a number of susceptibility loci and genomic sites but no causal gene(s) with a proven mechanism of action. Recent genome-wide gene expression studies on brains from schizophrenia patients and their matched controls have identified a number of genes that show an alteration in expression in the diseased brains. Although it is not possible to offer a cause and effect association between altered gene expression and disease, such observations support a neurodevelopmental model in schizophrenia. Here, we offer a mechanism of this disease, which takes into account the role of developmental noise and diversions of the neural system. It suggests that the final outcome of a neural developmental process is not fixed and exact. Rather it develops with a variation around the mean. More important, the phenotypic consequence may cross the norm as a result of fortuitous and/or epigenetic events. As a result, a normal genotype may develop as abnormal with a disease phenotype. More important, susceptible genotypes may have reduced penetrance and develop as a normal phenocopy. The incidental episodes in neurodevelopment will explain the frequency of schizophrenia in most populations and high discordance of monozygotic twins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Brain / growth & development
  • Epigenesis, Genetic*
  • Genetic Predisposition to Disease
  • Humans
  • Models, Neurological*
  • Risk Factors
  • Schizophrenia / etiology*
  • Schizophrenia / genetics
  • Twins, Monozygotic / genetics