Single‐nucleotide polymorphisms in genes related to the hypothalamic‐pituitary‐adrenal axis as risk factors for posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder. The etiology of PTSD is multifactorial, depending on many environmental and genetic risk factors, and the exposure to life or physical integrity-threatening events. Several studies have shown significant correlations of many neurobiological findings with PTSD. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is strongly correlated with this disorder. One hypothesis is that HPA axis dysfunction may precede the traumatic event, suggesting that genes expressed in the HPA axis may be involved in the development of PTSD. This article reviews molecular genetic studies related to PTSD collected through a literature search performed in PubMed, MEDLINE, ScienceDirect, and Scientific Electronic Library Online (SciELO). The results of these studies suggest that several polymorphisms in the HPA axis genes, including FKBP5, NR3C1, CRHR1, and CRHR2, may be risk factors for PTSD development or may be associated with the severity of PTSD symptoms.

Genes and hormones of the hypothalamic–pituitary–adrenal axis in post-traumatic stress disorder. What is their role in symptom expression and treatment response?

“…The heritability of PTSD is estimated at between 30 and 70% (Daskalakis et al 2018 ), and a number of genes known to encode different components of the HPA axis appear to be partly responsible for this. According to a systematic review of the literature, the Bcl1 single nucleotide polymorphism (SNP) within NR3C1 and four SNPs within FKBP5 (rs1360780, rs3800373, rs9296158, rs9470080) are particularly prominent HPA axis related risk factors for the development of PTSD (Carvalho et al 2017 ). A recent meta-analysis confirmed the role of NR3C1 and FKBP5 in PTSD, with rs258747 and rs9296158 emerging as significant risk-enhancing SNPs (Sheerin et al 2020 ).…”

The stressed brain of humans and rodents

“…How could such an imbalance between the rapid and delayed phases of the behavioural response to stress develop? Most likely, the system may become gradually unhinged due to an accumulation of life events, particularly in individuals with variations in genes encoding for critical molecules in the stress signalling pathway, associated with aberrant functionality of these molecules, such as has been described for the glucocorticoid receptor or FKBP5 . Especially, events taking place early in life, when both the stress system and the brain are still developing, are known to have a strong impact .…”

“…Most likely, the system may become gradually unhinged due to an accumulation of life events, particularly in individuals with variations in genes encoding for critical molecules in the stress signalling pathway, associated with aberrant functionality of these molecules, such as has been described for the glucocorticoid receptor or FKBP5. [23][24][25] Especially, events taking place early in life, when both the stress system and the brain are still developing, are known to have a strong impact. [26][27][28] This has been studied in detail in rodent models of early life adversity, which have the advantage of control over the genetic background, the (early life) environment and allow detailed investigations of the underlying mechanism ( Figure 5).…”

The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population

“…The CRHR1 gene and the CRHR2 gene regulate the HPA axis together by binding their encoding products, corticotropin-releasing hormone (CRH) receptors CRF1 and CRF2, to CRH. The CRHR1 gene has been suggested to be associated with PTSD (31)(32)(33)(34)(35)(36). The CRHR2 gene has been shown to significantly affect PTSD (32,37,38) as well as through a gene-environment interaction (39).…”

“…The CRHR1 gene has been suggested to be associated with PTSD ( 31 – 36 ). The CRHR2 gene has been shown to significantly affect PTSD ( 32 , 37 , 38 ) as well as through a gene–environment interaction ( 39 ).…”