In the remainder of this review, we select examples from studies in rodents modeling the intergenerational and transgenerational transmission of environmentally induced phenotypes with regard to psychiatric phenotypes. Epigenetic mechanisms of gene regulation have been posited as being critical to such transmission and inheritance. Besides direct exposure to stress both in utero and in early life, recent studies in rodents also point toward a transmission, and even inheritance, of environmentally accumulated risk factors via the germline that may occur prior to conception. However, animal models, in contrast, provide valuable insights into the molecular mechanisms of how the environment contributes to risk and resilience. Human studies using a cross-sectional design can and have investigated the overall influence of severe stress or childhood abuse on the risk for psychiatric disorders without having access to neuronal tissue for further analyses. These factors can exert a profound influence on disease trajectories when they occur during vulnerable periods in brain development like in utero development and early life until completion of adolescence, subsequently increasing the risk for mental health problems in adulthood ( Kessler et al, 1997 Kendler et al, 2000). Such factors have regained attention in the post-genomic era in recent years. Alternative models such as gene by environment interaction studies take this dual influence into account and may provide more insight into the pathophysiology of these disorders in the future ( Klengel and Binder, 2013a Manuck and McCaffery, 2014 Zannas, Wiechmann, Gassen and Binder, this issue).Įnvironmental factors influencing the long-term risk for psychiatric disorders have been known for centuries. The underlying reasons likely involve a larger genetic, but also phenotypic, heterogeneity and a stronger influence of the environment ( Levinson et al, 2014). Additionally, several other moderately powered GWAS have begun to identify genome-wide level significant findings ( Guffanti et al, 2013 Logue et al, 2013 Nievergelt et al, 2015). The genomics of PTSD is more nascent, and it is too early to tell which trajectory this disorder will have with regards to genetic contribution, though twin studies suggest up to 40% heritability. In contrast to the successful genetic studies for schizophrenia or bipolar disorder ( Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014 Muhleisen et al, 2014), studies on depression so far have failed to identify reliable genetic markers at sample sizes at which first loci in schizophrenia were identified ( Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, 2012). Although much effort is spent on studies investigating the genetic basis of psychiatric disorders and outstanding emerging studies point toward a polygenic risk to disease ( Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014), the overall contribution of genetic factors appears to be rather small in particular for stress and fear disorders based on our current knowledge ( Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, 2012 Sullivan et al, 2012 Wray et al, 2012 Lee et al, 2013 Levinson et al, 2014). It is widely accepted that environmental and genetic factors contribute to the development of psychiatric disorders. Our understanding of the molecular mechanisms of risk and resilience for disease is pivotal for the development of effective preventative and therapeutic strategies that are superior to the currently available limited therapies. Additionally, stress-related disorders demand increasing medical and economical resources and are predicted to become the leading cause of disability worldwide in the near future ( Wittchen et al, 2011 Whiteford et al, 2013). Changing environmental conditions with respect to not only socioeconomic status, social interactions, trauma exposure, and workload, but also nutritional status, may contribute to this phenomenon and thus potentially lead to a self-reinforcing risk for disease. The pervasiveness of these disorders is increasing in the public perception and recent studies support this view, although there is some controversy with regard to the underlying causes ( Heimberg et al, 2000 Kessler et al, 2005 Compton et al, 2006 Hidaka, 2012). Stress-related psychiatric disorders such as major depression, posttraumatic stress disorder (PTSD), and other anxiety disorders are highly prevalent in the general population ( Kessler et al, 2005), with an even higher prevalence in military and socioeconomically disadvantaged populations ( Hoge et al, 2004 Gillespie et al, 2009).
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