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

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298-0126, USA.
Disease markers (Impact Factor: 1.56). 04/2011; 30(2-3):89-99. DOI: 10.3233/DMA-2011-0761
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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 corticotrophin-releasing 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.

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Available from: Jordan W Smoller, Feb 13, 2014
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    • "; Maniam, Antoniadis, & Morris, 2014; Nicolaides, Charmandari, Chrousos, & Kino, 2014; Stratakis & Chrousos, 1995; Raison & Miller, 2003; Tsigos & Chrousos, 1994; Young, 1998). PTSD has been associated with a range of changes in HPA axis, including elevated levels of the CRH/CRH type 1 receptor (CRHR1) system (Amstadter et al., 2011; White et al., 2013; Wolf et al., 2013), low cortisol levels (T. Chen, Guo, et al., 2014; Horn, Pietrzak, Corsi-Travali, & Neumeister, 2014; Wahbeh & Oken, 2013; Yehuda, Engel, et al., 2005), and increased sensitivity of GR (Lehrner et al., 2014; Yehuda, Cai, et al., 2009). "
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    ABSTRACT: Post-traumatic stress disorder (PTSD) widely occurs among victims or witness of disasters. With flashbacks, hyperarousal, and avoidance being the typical symptoms, PTSD became a focus of psychological research. The earthquake in Wenchuan, China, on May 12, 2008, was without precedent in magnitude and aftermath and caused huge damage, which drew scientists' attention to mental health of the survivors. We conducted a systematic overview by collecting published articles from the PubMed database and classifying them into five points: epidemiology, neuropathology, biochemistry, genetics and epigenetics, and treatment. The large body of research during the past 6 years showed that adolescents and adults were among the most studied populations with high prevalence rates for PTSD. Genomic and transcriptomic studies focusing on gene × environment studies as well as epigenetics are still rare, although a few available data showed great potential to better understand the pathophysiology of PTSD as multifactorial disease. Phytotherapy with Chinese herbs and acupuncture are rarely reported as of yet, although the first published data indicated promising therapy effects. Future studies should focus on the following points: (1) The affected populations under observation should be better defined concerning individual risk factor, time of observation, spatial movement, and individual disease courses of patients. (2) The role of social support for prevalence rates of PTSD should be observed in more detail. (3) Efficacy and safety of Chinese medicine should be studied to find potential interventions and effective treatments of PTSD. © The Author(s) 2015.
    Trauma Violence & Abuse 05/2015; DOI:10.1177/1524838015585313 · 3.27 Impact Factor
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    • "These HPA axis effects occur, in part, through enhanced sensitivity of the glucocorticoid receptor (GR)-mediated feedback mechanism that suppresses stress-induced cortisol release (van Zuiden et al., 2012). Two small studies reported associations between PTSD and cannabinoid receptor (CNR1) gene variants (NM_016083 and NM_033181; (Lu et al., 2008), and between a SNP in corticotropin-releasing hormone receptor-1 (CRHR1, rs12944712) and PTSD onset in paediatric injury patients (Amstadter et al., 2011). "
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    ABSTRACT: Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30-40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions.
    The International Journal of Neuropsychopharmacology 10/2013; 17(2):1-16. DOI:10.1017/S1461145713001090 · 4.01 Impact Factor
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    • "3. CRHR1 (rs12944712; chromosome 17q21): Corticotrophin releasing hormone (CRH) is a hormone involved in regulating the stress response via the hypothalamic-pituitary-adrenal (HPA) axis. Multiple variants in the gene encoding the CRH type 1 receptor (CRHR1) have been associated with depression and anxiety both alone and in interaction with exposure to child abuse and trauma (Bradley et al., 2008; Amstadter et al., 2011). 4. FKBP5 (rs1360780, rs9296158, and rs9470080, chromosome 6p21): FKBP5 encodes a negative regulator of glucocorticoid receptor function. "
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    ABSTRACT: There is considerable variation in psychological reactions to natural disasters, with responses ranging from relatively mild and transitory symptoms to severe and persistent posttraumatic stress (PTS). Some survivors also report post-traumatic growth (PTG), or positive psychological changes due to the experience and processing of the disaster and its aftermath. Gene-environment interaction (GxE) studies could offer new insight into the factors underlying variability in post-disaster psychological responses. However, few studies have explored GxE in a disaster context. We examined whether ten common variants in seven genes (BDNF, CACNA1C, CRHR1, FKBP5, OXTR, RGS2, SLC6A4) modified associations between Hurricane Katrina exposure and PTS and PTG. Data were from a prospective study of 205 low-income non-Hispanic Black parents residing in New Orleans prior to and following Hurricane Katrina. We found a significant association (after correction) between RGS2 (rs4606; p=0.0044) and PTG, which was mainly driven by a cross-over GxE (p=0.006), rather than a main genetic effect (p=0.071). The G (minor allele) was associated with lower PTG scores for low levels of Hurricane exposure and higher PTG scores for moderate and high levels of exposure. We also found a nominally significant association between variation in FKBP5 (rs1306780, p=0.0113) and PTG, though this result did not survive correction for multiple testing. Although the inclusion of low-income non-Hispanic Black parents allowed us to examine GxE among a highly vulnerable group, our findings may not generalize to other populations or groups experiencing other natural disasters. Moreover, not all participants invited to participate in the genetic study provided saliva. To our knowledge, this is the first study to identify GxE in the context of post-traumatic growth. Future studies are needed to clarify the role of GxE in PTS and PTG and post-disaster psychological responses, especially among vulnerable populations.
    Journal of Affective Disorders 10/2013; 152(1). DOI:10.1016/j.jad.2013.09.018 · 3.38 Impact Factor
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