PTSD Linked to Epigenetic Changes in Immune Function Genes

Jacquelyn K. Beals, PhD

May 04, 2010

May 4, 2010 — Individuals who experience traumatic events leading to posttraumatic stress disorder (PTSD) demonstrate altered DNA methylation levels — especially in genes related to immune function, according to a study published online May 3 in the Proceedings of the National Academy of Sciences of the United States of America.

Investigators obtained DNA from whole blood samples of 100 individuals participating in the Detroit Neighborhood Health Study (DNHS). PTSD prevalence in this population was more than double that found in other studies, possibly due to high levels of exposure to violent assault, reported by 50.8% of DNHS participants.

Among 100 individuals in the present study, 23 were classified as having "lifetime PTSD" based on 6 diagnostic criteria, which must include exposure to a traumatic stressor that involves threat of death or severe injury or witnessing or learning about such an event affecting a close associate or family member; the response includes feelings of horror, helplessness, or fear.

Additional criteria include repeatedly reexperiencing the event; avoiding stimuli associated with the event, along with a decrease in normal responsiveness; and persistently increased arousal. The symptoms must persist 1 month or more, causing distress in or impairing normal social or professional functions.

14,000 Genes Analyzed

The new study analyzed methylation profiles of more than 14,000 genes in the 23 individuals clinically diagnosed as having PTSD and the 77 also exposed to one or more potentially traumatic events (PTEs) but not meeting PTSD criteria. With 0 representing unmethylated and 1 representing completely methylated, this study defined the cutoff for unmethylated as probe results less than 0.2 and methylated as greater than 0.8.

The results showed that the "number of uniquely unmethylated genes did not differ significantly between PTSD-affected and unaffected individuals." However, a significant difference existed between the groups in terms of the number of uniquely methylated genes (P < .0001).

Although some uniquely methylated genes were found in each group, there were fewer in the PTSD-unaffected group (methylation typically accompanies decreased gene expression).

More interesting than the number of uniquely methylated or unmethylated genes were the types of genes affected. In PTSD individuals, functional annotation clustering (FAC) analysis showed that the top 3 functional clusters of uniquely unmethylated genes in PTSD-affected individuals related to inflammatory response, immune response, and innate immune response. Corresponding analysis of non-PTSD individuals identified clusters of genes related to development, neurogenesis, and intracellular organelles.

FAC analysis of the genes uniquely methylated identified signaling, sound perception, and response to xenobiotic stimulus as top-ranked clusters in PTSD individuals, whereas signaling, lipase activity, and calcium ion binding were top ranked in non-PTSD individuals.

The investigators examined immune functions in PTSD individuals more closely by assessing antibody levels to cytomegalovirus (CMV), recognized as a "sentinel biomarker" of immune system compromise. The levels of CMV-specific antibody differed significantly between the PTSD and non-PTSD groups, being higher in the PTSD-affected group (P = .016).

Indicator of Immunocompromise

"Higher antibody level in this case represents immunocompromise," senior author Sandro Galea, MD, MPH, DrPH, professor and chair of the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, told Medscape Psychiatry.

"Everybody has CMV, but the more CMV one has, that is thought to be a sign of immunosenescence, immunocompromise. The fact that there are more antibodies suggests that there is immunosenescence...there is more antibody to something that we don’t expect to have so much of."

Many individuals experience more than 1 PTE, and other studies have suggested a relationship between the number of PTEs and PTSD severity. The present study analyzed the correlation between the number of PTEs experienced and level of methylation at each site on the microarray.

Relative to non-PTSD individuals, PTSD-affected individuals had almost 6 times more genes that correlated negatively with the number of PTEs they had experienced and almost 7 times more genes correlated positively with the number of PTEs experienced (P < .01). "A distinct signature of immune-related methylation profiles" was evident only in the PTSD-affected group.

Asked whether people with certain methylation profiles are just more vulnerable PTSD, Dr. Galea said. "Basically, we think that what we are seeing is trauma being associated with methylation epigenetic changes. The reason we think that is because we have evidence for dose response between traumatic event exposure and methylation.

"The more traumatic events people have, the more methylation changes they have — which of course would be unlikely that the methylation changes preceded the traumatic events," he added.

"It's not definitive," Dr. Galea acknowledged. "We can't be definitive with a cross-sectional study, but it's suggestive. The only way we can say it definitely is with a prospective study."

A Great First Look

"This is always a challenge with cross-sectional data," Dani Fallin, PhD, assistant professor, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, told Medscape Psychiatry. "I think these findings are a great first look, but the authors are right to point out that further longitudinal data is important."

"However, either interpretation could provide important information," Dr. Fallin continued. "If these epigenetic changes precede PTSD symptoms, this could inform the mechanism of PTSD. If instead, these serve as markers of the PTSD process once it has begun, this could provide insight into the natural progression biologically."

Dr. Galea and Dr. Fallin have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online May 3, 2010.