Shakespeare left out a crucial component for understanding human behavior when he wrote:

it is not in the stars to hold our destiny but in ourselves.

Our genetic predispositions are only part of the equation when it comes to determining our risk for developing psychiatric disorders. Exposure to stressful environments during critical periods of brain development plays a dramatic role in changing gene function and influencing response to traumatic events in adulthood.

The National Institute of Mental Health defines post-traumatic stress disorder (PTSD) as an anxiety disorder arising in the aftermath of living through a dangerous or traumatic event. In PTSD the “fight-or-flight” response to fearful stimuli is activated in situations where it is not necessary for the body to defend itself from harm. It does not affect every individual who has been exposed to trauma. A major question in the field is how variations at the molecular level alter the likelihood that a person will develop PTSD.

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In an insightful paper recently published in Nature Neuroscience, Klengel et al. shed light on the mystery of how genetic variability and life experiences alter our chances for developing neuropsychiatric disorders later in life. The authors identified single nucleotide polymorphisms (SNPs) (DNA sequence variations that differ across members of the population) in the FKBP5 geneA sequence of nucleic acids that forms a unit of genetic inh... More. Variations in this gene alone were not enough to predict adult PTSD, but if the individual had been exposed to trauma as a child and had the genetic variation, the chances increased. Gene-environment interaction is a term used to explain situations where an individual’s likelihood of having a particular disorder or disease is dependent on a risk allele that arises from exposure to a specific environment early in life.

The researchers continued their quest by pinpointing the specific DNA change underlying the increased risk for developing PTSD later in life. During development, our DNA undergoes changes that result in the addition or removal of methyl groups. Methylation modifies DNA and can result in increased expression of a particular gene or gene silencing. Traumatic events can change DNA methylation beginning during development and continuing through adulthood. The researchers observed that FKBP5, which is a risk allele for a stress response regulator, had an altered methylation state in children exposed to trauma.

In order to understand how SNPs and childhood experience could potentially interact to predict an adult disorder, it is crucial to understand the role of FKBP5. FKPB5 regulates the glucocorticoid system by suppressing activity. Glucocorticoids are released in response to stress. The SNP that is associated with risk for PTSD is located near the glucocorticoid response element. Adversity in early life resulted in fewer methyl groups in the blood of individuals who carried the risk allele in comparison to those who were not exposed to early life trauma or were not carriers for the PTSD predicting variant. In summary, demethylation in individuals with the risk variant of FKPB5 who were also exposed to early life trauma resulted in increased expression of FKBP5 that resulted in an abnormal response to stress.

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Demethylation of a methylation site in the risk allele occurs during a critical period during development. The result is activation of FKBP5 throughout life in the central nervous systemThe brain and spinal cord.. Stress during adulthood releases glucocorticoids that result in strong activation of the demethylated FKBP5. These individuals have a resistance to glucocorticoids that is associated with PTSD.

Unraveling the molecular mechanisms underlying the interactions between early trauma, brain development, and risk variants in specific genes has the potential to shed insight on why certain individuals develop major depression and PTSD in adulthood.

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Written by Jillian Shaw

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References:

Julius Caesar (I, ii, 140-141)

Klengel T., Mehta D., Anacker C., Rex-Haffner M., Pruessner J.C., Pariante C.M., Pace T.W.W., Mercer K.B., Mayberg H.S., Bradley B. & Nemeroff C.B. (2012). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions, Nature Neuroscience, 16 (1) 33-41. DOI:

Szyf M. (2012). How do environments talk to genes?, Nature Neuroscience, 16 (1) 2-4. DOI:

Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College.After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year.A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience.Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration.When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

Jillian L. Shaw

View posts by Jillian L. Shaw
Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

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