A new study offers an epigenetic explanation as to why some people are more reactive to stress or more vulnerable to disorders related to stress. A team of researchers at Duke University have found that methylation of a gene linked to post-traumatic stress disorder (PTSD) and clinical depression can affect how an individual reacts to threats or stress.
Recently published online in the journal Nature Neuroscience, the results highlight the link between the common epigenetic mechanism of DNA methylation and serotonin transporter gene expression. The serotonin transporter gene (SLC6A4) encodes for the serotonin transporter, a molecule responsible for transport of serotonin from the synaptic cleft back into the presynaptic neuron, known as reuptake. It has been the target for many treatments of depression and mood disorders.
“We decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it’s one of the best characterized genes in neuroscience,” said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.
“If we’re going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of,” Hariri said.
Their work contributes to an ongoing Duke Neurogenetics Study (DNS), an effort to comprehensively study the link between genes, brain activity, and other biological markers to young peoples’ risk for mental illness.
Eighty college-aged participants of the DNS underwent non-invasive brain imaging while looking at images of angry or fearful faces. The researchers recorded the responses of their amygdala, a part of the brain’s limbic system that, among other roles, controls the behavioral and biological responses to threatening or stressful stimuli. The team, in collaboration with Karestan Koenen at Columbia University’s Mailman School of Public Health in New York, also collected the saliva of participants to analyze the methylation of the serotonin transporter DNA.
Results indicated that the more the serotonin transporter DNA was methylated, the greater the reactivity of the amygdala. This bolstered reactivity by the amygdala may contribute to an increased stress response and vulnerability to disorders such as PTSD, Obsessive-Compulsive Disorder (OCD), Social Anxiety Disorder (SAD), or other stress-related disorders.
“To our surprise, even small methylation variations were sufficient to create differences between the students’ amygdala reactivity,” said lead author Yuliya Nikolova, a graduate student involved in the study. “The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with a risk for depression and anxiety.”
While excited, the researchers were also cautious of their findings because numerous studies in genetics have never been successfully replicated.
Jumping on the opportunity to replicate the study using a different group of participants, they collaborated with the University of Texas Health Science Center in San Antonio and observed the same pattern – this time even stronger – in individuals ages 11 to 15 from the Teen Alcohol Outcomes Study (TAOS).
With help from the director of TOAS, Douglas Williamson, the team measured the amygdala’s response to the same fearful and angry faces and analyzed serotonin transporter gene methylation using DNA from the blood of 96 adolescents. They found that the connection between methylation and amygdala reactivity was even stronger in this case.
“Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation,” Hariri said. The initial study reported under seven percent.
To strengthen the study even further, the researchers analyzed methylation patterns in the brains of deceased people, in collaboration with Etienne Sibille at the University of Pittsburgh, who is now at the Centre for Addiction and Mental Health in Toronto.
The results were consistent with their previous findings: increased methylation of the serotonin transporter gene at a particular location was linked to a decrease in serotonin transporter expression in the amygdala.
“That’s when we thought, ‘All right, this is pretty awesome,’” Hariri said.
Their discovery illuminates a connection between greater methylation and decreased gene expression of the serotonin transporter. The methylation of this particular gene, SLC6A4, appears to alter serotonin signaling, thereby affecting amygdala reactivity.
According to Nikolova, “This region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it.”
The researchers’ future plans involve investigating the methylation patterns of other genes among the serotonin system that could affect the brain’s stress response. The results of this study may also shed light on the inheritance of epigenetic marks, particularly DNA methylation, because of the similarity they found in the methylation patterns in blood, brain, and saliva.
Hariri hopes researchers investigating mental illness biomarkers will assess methylation “above and beyond DNA sequence-based variation and across different tissues.”
Source: Learn all about it and read more about their findings here: Beyond genotype: serotonin transporter epigenetic modification predicts human brain function. Yuliya S Nikolova, Karestan C Koenen, Sandro Galea, Chiou-Miin Wang, Marianne L Seney, Etienne Sibille, Douglas E Williamson & Ahmad R Hariri. Online August 2014.
References: Duke University. Small DNA Modifications Predict Brain’s Threat Response. August 2014.