Non-Genetic Transmission of Genetic Risk: Mechanism and Relevance to Psychiatric

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Linked publications & trials

Abstract

Abstract Gene variants and mutant genes have recently been identified in psychiatric disorders including anxiety disorders, depression, schizophrenia and attention deficit hyperactivity disorders. These disease associated genes are considered to be purely genetic factors in disease because their effects are believed to manifest when they are inherited. However, disease causing mutations or gene variants in parent-offspring triads may have a dual impact: the classical genetic effect and an additional environmental effect. Indeed, disease associated genes in the mother/parents, by altering maternal physiology or parental care, create an adverse environment for the offspring, that in turn, can lead to psychopathology. The importance of the non-genetic transmission of genetic risk is that it can significantly contribute to disease pathogenesis and increase the number of individuals at risk for psychiatric disease (because genetically normal individuals are also affected). During testing this dual impact idea of disease pathogenesis in two genetic animal models we realized that the maternal/parental environmental effect and the genetic effect in the offspring often result in similar long-lasting behaviors. We propose that the maternal/parental environmental effect and the genetic effect converge on vulnerable neurons causing epigenetic changes in their genome. Epigenetic changes include methylation of cytosines at CpG sites and secondary histone modifications that, similarly to genetic mutations, can permanently alter gene expression. These adverse epigenetic changes would impact the overall development and/or function of the affected neurons, manifested as permanent behavioral alterations. Here we propose to map epigenetic changes in the entire genome of affected neurons because characterization of the epigenome would help to understand how the various effects are integrated at the genome level and translated to an abnormal behavioral output. Importantly, the treatment and prevention of maternal/parental effects will likely be different from the treatment of symptoms caused by direct genetic effects. In contrast to genetic mutations, non-genetic transmission occurs after conception and often during postnatal development. This opens up opportunities to develop unconventional therapeutic approaches that could increase the specificity of treatments and avoid side effects associated with current medications.