Corticotrophin-Releasing Hormone Type 1 Receptor Gene (CRHR1) Variants Predict Posttraumatic Stress Disorder Onset and Course in Pediatric Injury Patients

Abstract

Abstract. Posttraumatic stress disorder (PTSD) is a common and disabling anxiety disorder that may occur in the aftermath of exposure to potentially traumatic life events. PTSD is moderately heritable, but few specific molecular variants accounting for this heritability have been identified. Genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, such as corticotrophinreleasing hormone type 1 receptor gene (CRHR1), have been implicated in traumatic-stress related phenotypes but have yet to be studied in relation to PTSD. The present study sought to examine the relation between 9 single nucleotide polymorphisms (SNPs) in the CRHR1 gene and posttraumatic stress symptoms in a prospective study of pediatric injury patients (n = 103) who were first assessed in the acute aftermath of their injury at the hospital. Results indicated that multiple SNPs were associated with acute symptoms at a univariate level, and after correction for multiple testing, rs12944712 was significantly related to acute PTSD symptoms. Longitudinal latent growth curve analyses suggest that rs12944712 is also related to both acute symptom level and trajectory of symptoms over time. The present study adds support for the role of CRHR1 in the stress response following potentially traumatic event exposure in youth. It should be noted that the sample size in this study was small, and therefore statistical power was low; following, results from this study should be considered preliminary. Although results are not definitive, the findings from this study warrant future replication studies on how variation in this gene relates to response to traumatic event exposure in youth.

Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene

“…We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, either showing a main effect for the genetic marker, and/or a significant GxE interaction (Amstadter et al, 2009(Amstadter et al, , 2011Binder et al, 2008;Boscarino et al, 2011;Cao et al, 2013;Comings et al, 1996;Dragan and Oniszczenko, 2009;Gillespie et al, 2013;Goenjian et al, 2012;Grabe et al, 2009;Guffanti et al, 2013;Hauer et al, 2011;Kolassa et al, 2010;Logue et al, 2013a,b;Lyons et al, 2013;Mellman et al, 2009;Nelson et al, 2009;Ressler et al, 2011;Segman et al, 2002;Solovieff et al, 2014;Voisey et al, 2010;Wilker et al, 2013;Xie et al, 2013). Since most studies were performed in subjects of either European or African descent, we used these specific ancestry groups for comparison with MRS. We found that most of the 25 candidate genes showed nominally significant associations in MRS for at least one of the SNPs tested.…”

“…Most research has focused on: (1) the hypothalamic-pituitary-adrenal (HPA) axis, (2) the ascending brainstem locus coeruleus noradrenergic system, and (3) the limbic amygdalar frontal pathway mediating fear processing. Among the over 25 PTSD candidate genes currently reported (Amstadter et al, 2009(Amstadter et al, , 2011Binder et al, 2008;Boscarino et al, 2011;Cao et al, 2013;Comings et al, 1996;Dragan and Oniszczenko, 2009;Gillespie et al, 2013;Goenjian et al, 2012;Grabe et al, 2009;Guffanti et al, 2013;Hauer et al, 2011;Kolassa et al, 2010;Logue et al, 2013a,b;Lyons et al, 2013;Mellman et al, 2009;Nelson et al, 2009;Ressler et al, 2011;Segman et al, 2002;Solovieff et al, 2014;Voisey et al, 2010;Wilker et al, 2013;Xie et al, 2013), promising findings include associations of PTSD symptoms with the serotonin transporter gene (SERT, SLC6A4) (Xie et al, 2009), which is linked to depression and anxiety disorders, as well as differential acquisition of conditioned fear and increased amygdala excitability in humans. In addition, FKBP5, a co-chaperone of the glucocorticoid receptor involved in the HPA axis, has a significant interaction with severity of child abuse in the prediction of adult PTSD symptoms, indicating a gene by environment (GxE) interaction (Binder et al, 2008).…”

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…Accordingly, targeted association studies were conducted to test whether CRHR1 polymorphisms -mainly rs7209436, rs110402, and rs242924, forming a haplotype where the TAT combination conveys disease -influence the risk for stress-related disorders like post-traumatic-stress disorder (PTSD; 13,14 ) and depression [15][16][17][18][19][20] .…”

Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults

“…B. Amstadter, Nugent, & Koenen, 2009; Koenen, 2007); however, CRH genes are seemingly particularly consequential (Baker et al, 2005; Smoller et al, 2005; Tyrka et al, 2009; van Gaalen, Stenzel-Poore, Holsboer, & Steckler, 2002). Of candidate gene studies of PTSD to date, few have examined genes influencing the HPA axis (Bachmann et al, 2005; Binder et al, 2008), with one prior study examining a CRH gene (A. B Amstadter et al, 2011).…”