Genome Advance of the Month
Child abuse leaves epigenetic marks
By Roseanne Zhao, Ph.D.
NIH Medical Scientist Training Program Track 3 Scholar
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In addition to harming the immediate wellbeing of the child, maltreatment and extreme stress during childhood can impair early brain development and metabolic and immune system function, leading to chronic health problems. As a consequence, abused children are at increased risk for a wide range of physical health conditions including obesity, heart disease, and cancer, as well as psychiatric conditions such as depression, suicide, drug and alcohol abuse, high-risk behaviors and violence.
They are also more susceptible to developing post-traumatic stress disorder (PTSD)-a severe and debilitating stress-related psychiatric disorder-after experiencing other types of trauma later in life.
Part of the explanation is that child abuse can leave marks, not only physically and emotionally, but also in the form of epigenetic marks on a child's genes. Although these epigenetic marks do not cause mutations in the DNA itself, the chemical modifications-including DNA methylation-change gene expression by silencing (or activating) genes. This can alter fundamental biological processes and adversely affect health outcomes throughout life.
New research, published in the May 14, 2013, issue of the Proceedings for the National Academy of Sciences, shows that PTSD patients who were abused as children have different patterns of DNA methylation and gene expression compared to those who were not.
Researchers from the Max Planck Institute in Germany and Emory University in the United States investigated whether the timing of trauma, specifically childhood abuse early in life, had an effect on the underlying biology of PTSD at the genome-wide level. To address this question, the authors examined a subset of 169 participants from the Grady Trauma Project-a survey of more than 5,000 individuals in Atlanta with a high lifetime exposure to multiple types of trauma, violence and abuse.
Among the 169 participants in the current study, most were African Americans in their late thirties and forties, and all had suffered from at least two types of trauma other than child abuse and seven types of trauma on average. In spite of multiple trauma exposure, the majority (108 people) did not develop PTSD. Of the 61 that did, however, 32 reported a history of childhood abuse and 29 did not.
To focus on the effect of childhood abuse in PTSD, the researchers examined genetic changes in peripheral blood cells from PTSD patients with and without previous exposure to childhood maltreatment. These were then compared to the trauma-exposed group that did not develop PTSD to rule out changes associated with trauma exposure alone.
Despite sharing a few common biological pathways, 98 percent of the changes in gene expression patterns in PTSD patients with childhood abuse did not overlap with those found in PTSD patients without childhood abuse. Interestingly, PTSD patients who experienced significant abuse as children exhibited more changes in genes associated with central nervous system development and immune system regulation, whereas those without a history of childhood abuse displayed more changes in genes associated with cell death and growth rate regulation.
Furthermore, the researchers found that epigenetic marks associated with gene expression changes were up to 12-fold higher in PTSD patients with a history of childhood abuse. This suggests that although all patients with PTSD may show similar symptoms, abused children who subsequently develop PTSD may experience a systematically and biologically different form of the disorder compared to those without childhood abuse.
What this means is that we may need to rethink our classification of PTSD and the notion of providing the same treatment for all PTSD patients, said Dr. Divya Mehta, corresponding author at the Max Planck Institute of Psychiatry.
"At the biological level, these individuals may be very distinct, as we see with the epigenetics," Dr. Mehta explained. "As we move forward with more personalized medicine, we will need to delve a bit further into the environment and history of each individual to understand the biology of their PTSD and to determine the best treatment for their disorder."
Although, it is currently unclear whether the epigenetic marks left by child abuse can be removed or the damage reversed, this discovery is important in the search for biomarkers with clinical indications that can be used to identify different forms of PTSD. This will help to direct more precise avenues for therapy and guide treatments tailored specifically to the biological process of individual patients.
By starting to distinguish subtypes of PTSD, this study highlights the multi-factorial nature of psychiatric disorders triggered by a combination of environmental and genetic factors. As the next step, Dr. Mehta and her team plan to study whether the age at which abuse occurs or the type of abuse affects the biology of PTSD.
Since even small changes in DNA methylation signatures in child abuse can have long-term implications for fundamental biological processes and health, Dr. Mehta hopes their research will also increase public awareness and strengthen efforts to protect children from the consequences of childhood abuse and neglect.
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