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.

Public Health Relevance

It is now well accepted that psychiatric disorders such as anxiety and depression have a genetic basis. Here we propose that, in addition to classical inheritance, gene variants or mutant genes can cause psychiatric disease in the offspring without being inherited from the parents. Specially, gene variants in the mother/parents, by altering maternal physiology or parental care, create an adverse environment for the offspring that in turn leads to psychopathology. Since the actual gene variant or mutant gene is not present in the affected offspring, the mechanism underlying the symptoms is not based on changes in the DNA sequence. Rather, we propose that secondary chemical modifications in the DNA and DNA associated proteins, called epigenetic changes, underlie the long-lasting disease symptoms in individuals exposed to adverse parental environment. The significance of the non-genetic transmission of disease risk is that children who did not inherit the genetic risk from their parents can also develop psychiatric disease symptoms. The risk associated with the non-genetic transmission however is not inevitable and could be mitigated by novel interventions that target the transmission mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086883-04
Application #
8280450
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2009-08-12
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$334,620
Indirect Cost
$136,620
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065