Post-traumatic stress disorder (PTSD) is one of the most important and severe mental disorders occurring in people who have been exposed to a series of traumatic events such as natural disasters, traffic accidents, war, or violent injuries (Javidi and Yadollahie, 2012; Lewis et al., 2019). This disorder shows complex symptoms involving flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the traumatic event, which can last for months or even years and interfere with daily life and work (Shalev et al., 2017). In the United States, the prevalence of PTSD among adults is 6%, and it is more common among women (9.7%) than among men (3.6%) (Harvard Medical School, 2007). As a serious psychological disorder, PTSD is not only an individual catastrophe but can also lead to serious psychological and financial burdens to the family and society (Hoppen et al., 2021). Although comprehensive etiological research has been conducted on PTSD, the underlying mechanisms of this disorder remain unclear.

Human dopaminergic neurons secrete a variety of hormones that regulate emotional behavior and are correlated with neuropsychiatric disorders (Grandy et al., 1989). Recent evidence had indicated a strong relationship between abnormal dopamine (DA) expression and mental or central nervous system diseases (Frankle et al., 2022; Joshi et al., 2022; Wenceslau et al., 2022). The dysregulation of dopaminergic function and signaling has been found to participate in several psychiatric disorders, such as attention-deficit hyperactivity disorder (ADHD) (Kim et al., 2018), alcohol dependence (Gorwood et al., 2000), schizophrenia (Hussain et al., 2020), and anxiety (Lawford et al., 2006).

Dopamine receptor D2 (DRD2) is a G protein-coupled receptor (GPCR) and is one of the most important intermediate transmitters of the dopaminergic system (Ford, 2014). This receptor is involved in dopamine signaling in presynaptic and postsynaptic neurons and is considered a key gene for PTSD (Yin and Chen, 2020). The current research suggests that DRD2 can activate the self-regulated synaptic pruning mechanism through the mTOR signaling pathway, and the deficiency of synaptic pruning in adolescents results in hyperglutamate function and anxiety-like behavior in adulthood (Yin and Chen, 2020; Zhang and Lin, 2021). Abnormal DRD2 expression and dopamine signaling dysfunction in several mental disorders have become critical therapeutic targets of antipsychotic drugs.

The DRD2 gene is located on human chromosome 11q23 and contains nine exons, several introns, and a short nucleotide repeat (STR) (Eubanks et al., 1992). To date, several single-nucleotide polymorphism (SNP) loci have been shown to be associated with PTSD susceptibility. Among these, rs1800497 C > T is the most common polymorphism locus, which is located 10.5 kb downstream of DRD2 and adjacent to the ankyrin repeat and kinase domain containing one gene (ANKK1) (Yin and Chen, 2020). This polymorphism encompasses a substitution of cytosine to thymine, and the minor T allele (the same as the A1 allele) always combines with the reduced number of dopamine-binding sites in the brain, resulting in a reduced level of dopaminergic activity (Pohjalainen et al., 1998). A recent neuroimaging study showed an association between the rs1800497 polymorphism and hippocampal function and volume, as well as PTSD severity. This was more specifically observed in TC carriers with reduced left CA3 volume and severe PTSD symptomatology (Yuan et al., 2022). In 1991, Comings et al. (1991) conducted the first case–control study on the association between the rs1800497 C > T polymorphism and PTSD susceptibility and reported a negative result in the US population. Since then, numerous studies have been published, but the results have been inconsistent or conflicting. Considering the uncertainty of the current results among published studies, we conducted a meta-analysis to assess the association between the rs1800497 C > T polymorphism and PTSD susceptibility.

The review and meta-analysis were performed in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009). All collected information was extracted from publications, and no ethical issues were involved.

Post-traumatic stress disorder is a common mental disease, and its incidence rate is gradually increasing. It is estimated that 7–8% of the global population suffers from PTSD at some point in their lives (Keane et al., 2006). PTSD always develops after exposure to a highly traumatic stress event. Violent personal assaults, natural or human-caused disasters, accidents, combat, and other forms of violence may be the most important triggers for PTSD. Many people often experience the impact of highly traumatic events, but only a small number eventually experience PTSD. Beyond intrinsic and environmental factors, increasing evidence suggests that genetic factors play a major role in the development and pathogenesis of PTSD. As a member of GPCR, DRD2 can inhibit the activity of adenylate cyclase, regulate the calcium potassium channel activity in neurons, and affect neuronal excitability and function. DRD2 belongs to the family of inhibitory D2-like receptors, which are mainly expressed at the synaptic end of dopaminergic neurons (Zhang and Lin, 2021). Tabano et al. (2022) found that DRD2 methylation levels can be modulated by stress conditions and are positively correlated with PTSD occurrence.

SNPs are the most common type of gene mutation in humans and contribute to individual susceptibility to several diseases through altered gene transcription, expression, and spatial structure. Some studies have suggested that the rs1800497 polymorphism is always accompanied by an abnormal expression of the DRD2 gene in the brain tissue and is associated with several psychiatric disorders, such as anxiety, depression, schizophrenia (Zhou et al., 2022), bipolar disorder (Zhang et al., 2021), and autism spectrum disorder (Liu, 2020). Rs1800497 was originally considered the DRD2 polymorphism locus in most published studies since it could regulate the synthesis of dopamine and reduce D2 receptor expression (Munaf et al., 2009). Thompson et al. (1997) and Jönsson et al. (1999) proved that individuals with the T allele show a decrease of 30–40% in DRD2 density in the striatum compared to wild-type genotype carriers, which is consistent with PTSD patients with dopamine hypoactivity (Lawford et al., 2006). Moreover, Klein et al. (2007) suggested that the replacement of an acidic amino acid (C allele) by a basic amino acid (T allele) was associated with decreased dopamine D2 receptor density/availability in the brain, resulting in decreased sensitivity to traumatic actions. However, the mechanism by which the rs1800497 polymorphism affects or regulates phenotypic expression remains unclear (Thompson et al., 1997). The rs1800497 locus is far from the RD2 gene and cannot affect the expression of the DRD2 gene directly. Therefore, linkage disequilibrium with other functional loci may be a reasonable explanation for the potential mechanism of lower DRD2 density (Pohjalainen et al., 1998). The TaqIA polymorphism has been speculated to be in linkage disequilibrium with mutations in the DRD2 gene or other adjacent genes, such as the rs6276 or rs6277 locus, which is also associated with a decreased expression of DRD2 mRNA (Jiang et al., 2014).

To date, several studies have been conducted to explore the association between the rs1800497 polymorphism and PTSD risk; however, the results remain inconsistent. Gelernter et al. (1999) conducted an early case-control study in 1999 and suggested that the rs1800497 mutation is unlikely to contribute to PTSD risk in US combat veterans. Voisey et al. (2009) and Dretsch et al. (2016) also reported similar results in Australian and US subjects. In contrast, Ning et al. reported an increased PTSD risk in Chinese individuals with mutated genotypes (homozygote contrast: OR = 1.43, 95% CI = 1.17–3.21; heterozygote contrast: OR = 1.77, 95% CI = 1.52–2.10). Tian et al. (2015) suggested that PTSD patients with earthquake experience in the Wenchuan earthquake in China presented a significantly higher TT homozygote rate than controls. Xiao et al. (2019) also reported increased PTSD risk in individuals with the TT genotype (OR = 2.39, 95% CI = 1.39–4.12). The inconsistent results may result from the following: (1) different PSTD causes; (2) different ethnicities and origin countries; (3) deviations of HWE; (4) different genotype assessment methods; and (5) quality differences in the included studies.

Therefore, how can we obtain a more precise result in the current situation? Meta-analysis may be the best choice to resolve the current inconsistencies among studies with larger pooled samples. In 2016, Li et al. (2016) conducted the first meta-analysis on this subject and suggested a significant association between the rs1800497 polymorphism and PTSD susceptibility. The pooled results were derived from six case-control studies involving only 597 patients with PTSD and 1,155 controls, without any subgroup analysis or other quality assessment. To date, more evidence has emerged, and therefore, we conduct this meta-analysis to more precisely assess the association between the rs1800497 polymorphism and PTSD susceptibility based on more eligible data.

In our meta-analysis, 12 observational studies (from 11 publications) involving 5,515 subjects were included. Scientific statistical methods with multiple analyses were employed, and the co-dominant genetic model was suggested as the most appropriate choice to examine the association between the rs1800497 polymorphism and PTSD susceptibility. Overall, the pooled results indicated a significant association between the rs1800497 polymorphism and PTSD susceptibility in the general population and several specific subgroups, such as control design, causes of trauma, and crowds. For TEWOP controls, our results indicate that the mutation of the rs1800497 polymorphism might be a more dangerous triggering factor when PTSD patients and TEWOP controls face the same traumatic exposures. Considering the causes of trauma, the current results indicated that the earthquake was more strongly correlated with PTSD risk than other factors. This may be because the occurrence of earthquakes is sudden and often unpredictable. In addition, earthquakes are more destructive in depth and breadth, and this damage always involves a wider range of people, and the personnel composition is more complex. For different crowds, the stratified analysis demonstrated that civilians were more vulnerable in the face of traumatic events. This also means that the ability of civilians to tolerate and resist high-intensity traumatic events is weaker than that of military personnel who have systematic training. Moreover, in co-dominant genetic models (heterozygote model and mutant homozygote model), the pooled results revealed a statistically significant difference in the general population and subgroups, which also indicated that the rs1800497 TT genotype could increase PTSD risk with a gene dosage effect compared with the CC genotype and the CT genotype. In terms of ethnic differences, six studies focused on Caucasian and Asian descendants, and the results showed that the T allele may be an independent trigger for PTSD risk in Asians but not in Caucasians. Even so, these results should be interpreted with caution because of the small sample size and obvious heterogeneity in Asian populations.

Inevitably, there were some limitations that should be addressed in our research. First, only one polymorphism locus was analyzed in this meta-analysis, and the interactions with other SNPs and the gene–gene or gene–environment synergistic effects could not be assessed due to the lack of original information. Second, moderate heterogeneity was observed in several genetic models, which might have caused bias in the current results. This heterogeneity was partially alleviated with subsequent stratified analysis, and no significant contributing factor was found in meta-regression analyses. Third, the current studies were mostly conducted with Caucasian and Asian descendants, and whether the results could be extended to the general population remains to be demonstrated. Nevertheless, some advantages of our meta-analysis should be highlighted: (1) Multivariate meta-analyses were applied in this study as a scientific statistical method to select a more appropriate genetic model, (2) complete search strategies and rigorous criteria of inclusion and quality assessment were employed, and (3) cumulative analyses and sensitivity analyses were conducted to identify potential interfering factors and to guarantee the credibility of our results.

In summary, this meta-analysis suggests that the DRD2/ANKK1 rs1800497 polymorphism may increase the risk of PTSD susceptibility. Due to the insufficient quantity and quality of published research, global, high-quality studies with larger sample sizes should be conducted to further validate the current results.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.

Y-MN, JZ, and Y-YH conceived the study. Y-MN, JZ, and HT searched the databases and extracted the data. Y-MN and L-HC analyzed the data. Y-MN, JZ, T-YJ, and Y-YH wrote the draft of the article. T-YJ and Y-YH reviewed the manuscript. All the authors approved the final manuscript.