Abstract
Previous studies suggest that genetic variants within genes affecting the circadian rhythm influence the development of posttraumatic stress symptoms (PTSS). In the present study, we used data from three emergency care-based cohorts to search genetic variants in circadian pathway genes previously associated with neuropsychiatric disorders for variants that influence PTSS severity. The three cohorts used included a discovery cohort of African American men and women enrolled following motor vehicle collision (n = 907) and two replication cohorts: one of multi-ethnic women enrolled following sexual assault (n = 274) and one of multi-ethnic men and women enrolled following major thermal burn injury (n = 68). DNA and RNA were collected from trauma survivors at the time of initial assessment. Validated questionnaires were used to assess peritraumatic distress severity and to assess PTSS severity 6 weeks, 6 months, and 1 year following trauma exposure. Thirty-one genetic variants from circadian rhythm genes were selected for analyses, and main effect and potential gene*stress and gene*sex interactions were evaluated. Secondary analyses assessed whether associated genetic variants affected mRNA expression levels. We found that six genetic variants across five circadian rhythm-associated genes predicted PTSS outcomes following motor vehicle collision (p < 0.05), but only two of these variants survived adjustment for multiple comparisons (False Discovery Rate < 5%). The strongest of these associations, an interaction between the PAR-zip transcription factor, thyrotroph embryonic factor (TEF) variant rs5758324 and peritraumatic distress, predicted PTSS development in all three cohorts. Further analysis of genetic variants in the genetic region surrounding TEFrs5758324 (±125,000 nucleotides) indicated that this allele showed the strongest association. Further, TEF RNA expression levels (determined via RNA-seq) were positively associated with PTSS severity in distressed individuals with at least one copy of the TEFrs5758324 minor allele. These results suggest that rs5758324 genetic variant in TEF, a regulator of clock-controlled genes and key mediator of the core circadian rhythm, influence PTSS severity in a stress-dependent manner.
Highlights
We searched among genetic variants in circadian pathway genes associated with neuropsychiatric disorders for variants that influence posttraumatic stress symptom severity after traumatic stress
We identified a genetic variant in the thyrotroph embryonic factor (TEF) gene, rs5758324, that had a stress-dependent influence on posttraumatic stress symptom severity across three different trauma exposures (MVC, Sexual Assault (SA), and major thermal burn injury (MThBI)) and across multiple ethnicities, such that individuals with peritraumatic distress and at least one copy of the minor allele had the highest levels of posttraumatic stress symptoms (PTSS) over time
A strong positive relationship between TEF mRNA expression and PTSS severity was observed in individuals with high levels of peritraumatic distress and at least one copy of the TEFrs5758324 minor allele, suggesting that the variant may be functional
Summary
Traumatic events are common in life. For instance, each year in the United States, more than 11 million individuals experience a motor vehicle collision (MVC) [1], more than one million women are sexually assaulted [2], and more than 50,000 individuals are hospitalized after major thermal burn injury [3]. The first GWAS for PTSS identified an association between genetic variants in the retinoidrelated orphan receptor alpha gene, a gene that stabilizes environmental influences on the circadian rhythm [7], and PTSS vulnerability [8]. This association has been subsequently replicated in both studies of PTSS [9, 10] and other stress-related disorders [11,12,13,14,15,16,17] [and failed to replicate for PTSS [18]]
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