Understanding posttraumatic stress disorder: insights from the methylome

Abstract

Genome-wide association studies (GWAS) have identified numerous disease-associated variants; however, these variants have a minor effect on disease and explain only a small amount of the heritability of complex disorders. The search for the missing heritability has shifted attention to rare variants, copy number variants, copy neutral variants and epigenetic modifications. The central role of epigenetics, and specifically DNA methylation, in disease susceptibility and progression has become more apparent in recent years. Epigenetic mechanisms facilitate the response to environmental changes and challenges by regulating gene expression. This makes the study of DNA methylation in psychiatric disorders such as posttraumatic stress disorder (PTSD) highly salient, as the environment plays such a vital role in disease aetiology. The epigenome is dynamic and can be modulated by numerous factors, including learning and memory, which are important in the context of PTSD. Numerous studies have shown the effects of early life events, such as maternal separation and traumas during adulthood, on DNA methylation patterns and subsequent gene expression profiles. Aberrations in adaptive DNA methylation contribute to disease susceptibility when an organism is unable to effectively respond to environmental demands. Epigenetic mechanisms are also involved in higher order brain functions. Dysregulation of methylation is associated with neurodevelopmental and neurodegenerative cognitive disorders, affective disorders, addictive behaviours and altered stress responses. A thorough understanding of how the environment, methylome and transcriptome interact and influence each other in the context of fear and anxiety is integral to our understanding and treatment of stress-related disorders such as PTSD.