(Epi)genomics and neurodevelopment in schizophrenia: monozygotic twins discordant for schizophrenia augment the search for disease-related (epi)genomic alterations.

Unlike stunning breakthroughs in the identification of genes for Mendelian disorders during the last three decades, gene identification in most complex disorders has been full of twists and turns and little progress. Doing more of the same will not guarantee success. The lessons learned argue for a need to reconsider genetic models that are appropriate for the disorder in question along with an interdisciplinary, systematic approach using genomic methods that have now become possible. We will use schizophrenia as an example to review the genetic progress to date that has been disappointing. We will argue that the causation of this complex disease may involve heterogeneous genomic changes of major effect. We will provide three approaches, retroviral transpositions, methylation, and copy number variations, to test this hypothesis. We will present arguments to suggest that such experiments will be most effective if undertaken on monozygotic twins. It will include our experience with associated experiments on the monozygotic twins discordant for schizophrenia. The results support that (epi)genomic changes of major effect, rather than accumulation of mutations of small effect, underlie the causation of this complex disease. More important, this experimental strategy will be an effective strategy for studies on other complex (behavioural) disorders as well.