Evaluation of the Association Between Genetic Variants in Circadian Rhythm Genes and Posttraumatic Stress Symptoms Identifies a Potential Functional Allele in the Transcription Factor TEF

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.

Forecasting individual risk for long-term Posttraumatic Stress Disorder in emergency medical settings using biomedical data: A machine learning multicenter cohort study

“…Also in the absence of non-traditional work patterns, nighttime trauma exposure may be specifically associated with acutely disturbed circadian rhythmicity and sleep. Circadian dysregulation is increasingly recognized as biological correlate of PTSD ( Dayan et al, 2016 ), and genetic variation in circadian rhythm are related to PTSD risk ( Linnstaedt et al, 2018 ). Additionally, pre-trauma blunted ultradian corticosterone patterns were found to be a vulnerability factor for PTSD-like behavior in rodents ( Danan et al, 2018 ).…”

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

“…Furthermore, the enrichment of genes associated with circadian rhythms was expected given the 20 wealth of PTSD research in this area, and the common presentation of PTSD with sleep dysfunction, including insomnia and nightmares. To name a few, studies revealed altered circadian rhythms of cortisol in individuals with PTSD (Yehuda et al, 1996), and association between PTSD and variants in circadian rhythm genes (Linnstaedt et al, 2018;Logue et al, 2013). Finally, the enrichment of the PSD-95 gene set aligns with substantial evidence 25 supporting a role for PSD-95 in synapse-related dysfunction in several neuropsychiatric disorders (Penzes et al, 2011).…”

Circadian rhythms in the blood–brain barrier: impact on neurological disorders and stress responses

“…RORA is involved in the REV-ERB loop that influences the molecular clock and has been identified as PTSD risk gene [ 220 , 221 ]. Another gene loop involved in the molecular clock, a PARb-ZIP factor, TEF (variant rs5758324), showed strong associations with PTSD symptoms [ 222 ]. These findings further emphasize wide reaching implications involved in circadian disruption.…”