The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder

Li, Lizhuo; Bao, Yijun; He, Songbai; Wang, Gang; Guan, Yanlei; Ma, Dongjie; Wang, Pengfei; Huang, Xiaolong; Tao, Shanwei; Zhang, Dewei; Liu, Qiwen; Yang, Jingyun

doi:10.1097/md.0000000000003074

Cited by 52 publications

(32 citation statements)

References 52 publications

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“…Among these were several PTSD-associated genes, either through polymorphisms associated with PTSD (Adcyap1 [Pacap], Bdnf and Drd2), or as members of neuromolecular systems known to be dysregulated in PTSD patients, such as catecholamines (TH, Drd1/2, DARP-32). In a PTSD metastudy, the rs1800497 polymorphism in DRD2 was associated with PTSD diagnosis (70). Bdnf and adcyap1 were also dysregulated in the amygdala of rats following a 15-shock SEFL protocol (45).…”

Section: Discussionmentioning

confidence: 99%

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

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Background The limited neurobiological understanding of PTSD has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible (SS) and –resilient (SR) subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. Methods We employed a SEFL paradigm in inbred male and female C57BL/6 that combines acute stress with fear conditioning to precipitate “traumatic” memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence and RNA-sequencing of the basolateral amygdala (BLA). Results Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without post-training phenotyping. Additional phenotyping of males revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization and dysregulated corticosterone in SS males. Altered Fos activation was also seen in the infralimbic cortex and BLA of SS males after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA-sequencing of the BLA revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to PTSD patients. Conclusions This SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.

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Section: Discussionmentioning

confidence: 99%

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

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“…A more recent meta-analysis [21] (including nine studies, four significant) found only trend-level support for an association. A meta-analysis of dopaminergic system genes [22] resulted in significant overall associations for DRD2 (rs1800497; five of six studies significant) and SLC6A3 (3’ UTR variable tandem repeat polymorphism; five of five significant), but no effect for COMT Val 158 Met, likely due to different directions of effect across the five included studies). These meta-analyses represent one way of summarizing existing evidence, highlight important factors such as differing directions of effect and utilizing a proper trauma-exposed control group, and represent a useful direction for continued efforts as the number of studies for additional polymorphisms increase.…”

Section: Molecular Geneticsmentioning

confidence: 99%

The genetics and epigenetics of PTSD: overview, recent advances, and future directions

Sheerin

Lind

Bountress

et al. 2017

Current Opinion in Psychology

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This paper provides a brief summary and commentary on the growing literature and current developments related to the genetic underpinnings of posttraumatic stress disorder (PTSD). We first briefly provide an overview of the behavioral genetic literature on PTSD, followed by a short synopsis of the substantial candidate gene literature with a focus on genes that have been meta-analyzed. We then discuss the genome-wide association studies (GWAS) that have been conducted, followed by an introduction to other molecular platforms used in PTSD genomic studies, such as epigenetic and expression approaches. We close with a discussion of developments in the field that include the creation of the PTSD workgroup of the Psychiatric Genomics Consortium, statistical advances that can be applied to GWAS data to answer questions of heritability and genetic overlap across phenotypes, and bioinformatics techniques such as gene pathway analyses which will further advance our understanding of the etiology of PTSD.

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“…For example, research examining the impact of genetic variants in the dopaminergic system and PTSD has yielded mixed results (e.g., Gelernter et al., ; Voisey et al., ). However, meta‐analyses suggest that the SNP rs1800498 in DRD2 and the 3’‐UTR variable number tandem repeat (VNTR) in SLC6A3 are significantly associated with PTSD (Li et al., ), whereas the association between rs4680 in COMT and PTSD was nonsignificant. To our knowledge, a meta‐analysis of the association between variants in ADCYAP1R1 and PTSD has not been conducted.…”

mentioning

confidence: 99%

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

Lind

Marraccini

Sheerin

et al. 2017

Journal of Traumatic Stress

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Recent studies point to the potential role of the (pituitary) adenylate cyclase activating polypeptide receptor 1 (ADCYAP1R1) gene, which has been implicated in stress response, in posttraumatic stress disorder (PTSD). Multiple genetic association studies have examined potential PTSD risk related to this gene, with mixed results. We conducted a meta-analysis of rs2267735 in ADCYAP1R1 in PTSD. A literature search was conducted using PubMed and PsycINFO, resulting in nine studies that met criteria for inclusion in analysis. Biostat’s Comprehensive Meta-Analysis was used to conduct the main meta-analysis on the combined sex sample, as well as two subanalyses examining effects separately in female and male participants. Results indicated that the C allele of rs2267735 conferred significant risk for PTSD in the combined sex data, OR = 1.210, 95% CI [1.007, 1.454], p = .042, and in the subsample of women and girls, OR = 1.328, 95% CI [1.026, 1.719], p = .031; but not in the subsample of men and boys, OR = 0.964, 95% CI [0.733, 1.269], p = .796. These results provide evidence for an association between ADCYAP1R1 and PTSD and indicate that there may indeed be sex differences. Implications of these findings, including the role of rs2267735 as one modulator of the stress system, are discussed.

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The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder

Abstract: Supplemental Digital Content is available in the text

Cited by 52 publications

References 52 publications

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

The genetics and epigenetics of PTSD: overview, recent advances, and future directions

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta‐Analysis

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