After a mass shooting on a college campus, young women carrying the 5-HTTLPR multimarker and rs25531 genotypes of the serotonin transporter gene exhibited significant PTSD symptom scores (P=0.03 and P=0.1, respectively), according to Kerry J. Ressler, MD, PhD, of Emory University in Atlanta, and colleagues.
In contrast, the STin2 polymorphism of the serotonin transporter gene, which has been linked with psychosis and suicidality, was not associated with PTSD symptoms (P=0.81), the researchers reported online in the Archives of General Psychiatry.
"One of the critical questions surrounding PTSD is why some individuals are at risk for developing the disorder following an index trauma while others appear to be relatively resilient," the researchers observed.
The role of genetics in PTSD was first demonstrated by twin studies among Vietnam War veterans, but molecular genetic data have not been fully explored.
Among the earlier studies that have examined genetic links with PTSD, significant associations were most commonly found for SLC6A4, which codes for the protein responsible for regulating serotonergic activity, 5HTT.
The so-called long/short polymorphism of this gene, 5-HTTLPR, has been shown to influence psychiatric disorders, with the shortened allele conferring heightened risks.
Another polymorphism in the same SLC6A4 gene, rs25531, is thought to modulate the expression of 5-HTTLPR, and the two polymorphisms together represent a multimarker genotype.
The researchers sought to assess the influence of this multimarker genotype, 5-HTTLPR alone, rs25531 alone, and another polymorphism in the serotonin gene referred to as STin2.
A unique set of circumstances enabled Ressler and colleagues to explore these concepts. On Feb. 14, 2008, a gunman killed five and wounded an additional 21 people on the campus of a university in northern Illinois.
Prior to this, more than 1,000 undergraduate women at the university had completed a questionnaire about sexual abuse and other traumatic experiences that could lead to PTSD, and 691 were interviewed following the shooting.
Genetic analyses for the serotonin polymorphisms were subsequently performed for 204 of the women, whose mean age was 20.
These 204 comprised the study sample.
The researchers first looked at factors that were associated with PTSD symptoms, and found significant associations with the following:
- Presence in the hall where the shooting took place (P<0.05)
- Hearing gunfire (P<0.005)
- Seeing the gunman (P<0.001)
- Seeing someone shot (P<0.05)
- Being hurt in the shooting (P<0.005)
"Proximity to the shooting was highly associated with PTSD symptom severity," they observed.
Further analysis determined that participants who carried the low-expressing variant of the 5-HTTLPR multimarker had significantly higher scores on the Distressing Event Questionnaire (DEQ) after the shooting than those with the high-expressing variant (mean DEQ score of 23.91 versus mean DEQ score of 18.42, P=0.007).
When the researchers then looked at the specific symptoms of PTSD, they found greater associations with avoidance (P=0.003) than for hyperarousal (P<0.05) or nightmares and flashbacks (ns).
They noted that it has been difficult to isolate the genetic factors that contribute to PTSD because of the potential confounders of level of exposure and previous history of trauma.
Because the students in this study had already been evaluated for stress and traumatic life events, this potential confounding was minimized, they said.
Their finding implicating the 5-HTTLPR shortened alleles in PTSD risk is "biologically plausible," according to the authors, because previous research has shown that having one shortened allele reduces the expression of the serotonin protein 5HTT by 27%. The presence of a second shortened allele diminishes the expression by 30%.
Limitations of the study included the relatively small number of participants having genotype analysis, and the fact that most of the post-shooting interviews took place less than a month after the event. The DSM-IV diagnosis of PTSD requires the presence of symptoms for longer than one month.
Only 35 of the women were interviewed after one month, and associations in this subgroup were nonsignificant.
Nonetheless, the researchers argued that their data support differences in functionality of the serotonin transporter gene with PTSD risk.
"When examined in a relatively homogenous sample with shared trauma and known prior levels of child and adult trauma, the 5-HTTLPR multimarker genotype may serve as a useful predictor of risk for PTSD-related symptoms in the weeks and months following the trauma," they concluded.
The study was funded by the Joyce Foundation, the Burroughs Wellcome Fund, the National Institute of Child Health and Human Development, and the National Institute of Mental Health.
The authors reported no financial disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner