Genetic biomarkers related to the population risks of posttraumatic stress disorder development: single nucleotide variants, gene interactions, and haplotypes

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Abstract

The increasing relevance of PTSD issues is associated with the escalation of military conflicts worldwide. Complex biological mechanisms also play a significant role in the pathogenesis of PTSD, including those changes observed in the hippocampus and other brain structures.

Aim – to identify the most significant genetic markers predisposing the risk of PTSD manifestation, which could contribute to the development of targeted interventions focusing on the preventive measures and treatment strategies of this disorder.

A literature search was conducted in the PubMed database using keywords related to the genetics of PTSD, with a publication time restriction from 2018 to 2023. Out of 623 papers, 20 articles met the inclusion criteria, describing molecular-genetic and statistical data, and the sample size of at least 60 patients with a verified PTSD diagnosis, were reviewed and analyzed in detail.

The studies revealed significant associations between PTSD occurrence and single nucleotide variants (SNVs) in the FKBP5 and CRHR1 genes. Particular attention was paid to the interactions between SNVs of different genes and their association with the severity of PTSD clinical manifestations.

Conclusions. Genetic markers, in particular, SNVs in the FKBP5 (rs9470080) and CRHR1 (rs1724402) genes, may play a key role as the risk factors for biological predisposition and the PTSD development. These findings would underlie the targeted interventions integrated into PTSD-related prevention measures and treatment strategies. However, further multicenter and consortium studies with unified design are required to confirm the significance of the identified associations and to specify the epigenetic aspects contributing to the PTSD manifestation and development.

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Список сокращений

ПТСР – посттравматическое стрессовое расстройство; ОНВ – однонуклеотидный вариант (замена, полиморфизм); ПАВ – психоактивное вещество; ДИ – доверительный интервал; ОШ – отношение шансов.

INTRODUCTION

Post-traumatic stress disorder (PTSD) is a mental illness originating in the delayed period after exposure to a severe or life-threatening psycho-traumatic event and characterized with a wide range of psychopathological manifestations. These include sudden responses to triggers i.e. phenomena of repeated experience of bright pictures associated with the psycho-traumatic event (flashbacks), fear, anxiety, somatic autonomic manifestations, various degrees of mental confusion, nocturnal sleep disturbances, anxiety dreams and behavioral disorders, viz. alcohol and substance abuse, which reduces overall quality of life and results in the development of social estrangement and social and professional maladaptation, respectively. According to WHO data, the average prevalence of PTSD worldwide is 3.6%, whereas other sources report higher percentages: 8% for women and 4% for men [1]. At the moment, the problem of PTSD has become of greater vitality due to escalation of military conflicts which are a significant factor in the progression of PTSD.

Complex biological mechanisms are involved in the formation of PTSD manifestations. The hippocampus plays an important role in the pathogenic mechanism of PTSD, specifically, the CA3 zone that regulates processes of memory pattern completion and separation that are vital for the formation of behavioral response and emotional processing of new experiences [2, 3]. In some studies, these changes are linked directly with the changes in the neuroplasticity and neurogenesis in the hippocampus that are seen in PTSD, when the regulatory balance between the activity of the mature and the young of the hippocampus is disrupted.

Besides, the studies identified a distributed system of brain structures including the central nucleus of the amygdala, frontal part of the hippocampus and the orbital prefrontal cortex which lies in the basis of the mechanism of imprinting of the type of stress reaction formed at an early age, which also actualizes under the onset of PTSD in adult age [4]. The ongoing long-term activation of the hypothalamo-pituitary-adrenal axis provides the biological foundation for the development of PTSD comorbid sequelae [5].

From the standpoint of existing neurobiological models, the impact of severe and life-threatening stress states and traumas starts up a self-sustaining mechanism of synaptic dysfunction, particularly, in the key neural networks of emotional regulation (the amygdala – ventral medial area of prefrontal cortex – supracallosal gyrus – hippocampus axis) [6]. Other researchers suggest that the changes encompass the thalamus and the cores of the striatum, dorsolateral and dorsomedial areas of prefrontal cortex, posterior cingulate cortex, and the involved sensory areas of cortex [7]. The results of meta-analysis of numerous studies indicate the change in the volume of subcortical areas, which might account for the stability of the clinical performance of PTSD many years since the exposure to the stress factors [8].

These mechanisms are considered the results of gene-environment interactions, and whereas the role of the environment factors seems obvious, the gene basis of PTSD formation requires deeper research [9]. Zhang et al. (2017) [10] summarized results of seven genome-wide association studies (GWAS) on large samples. In these studies, most frequently identified genes were FKBP5 (involved in the endocrine regulation), ADCYAP1R1 (regulator of the signal path function), NR3C1 (glucocorticoid receptor), DRD2 (dopamine receptor linked to various neuropsychiatric conditions), CRHR1 (corticotropin-releasing hormone receptor) and SLC6A4 (serotonin transporter in plasma membrane). It is of no less importance that these genes are expresses in the aforementioned areas of the brain associated with PTSD mechanisms [10].

We are of the opinion that single-nucleotide variants (SNVs) of these genes and their epistasis and interaction with environment factors might affect formation of susceptibility to development of PTSD.

AIM OF REVIEW

To identify among the aforementioned genes the most significant genetic markers predisposing the risk of PTSD manifestation, which could contribute to the development of targeted interventions focusing on the preventive measures and treatment strategies of this disorder.

MATERIAL AND METHODS

In order to perform the literature search in the optimal way, it was divided in two stages: first, we identified the suitable genes and polymorphisms and then performed a detailed analysis of candidate genes for the PTSD susceptibility using PubMed as the general database. We ran the first stage of search using the following keywords: «PTSD genetic markers», «PTSD genetics», «PTSD genetic polymorphism». The second stage included queries to search for specific genes identified in the first stage: «FKBP5 and PTSD», «ADCYAP1R and PTSD», «NR3C1 and PTSD», «DRD2 and PTSD», «DRD4 and PTSD», «CRHR1 and PTSD», «SLC6A4 and PTSD», «CRHR2 and PTSD». The search yielded 623 publications, of which 20 met our criteria for the detailed analysis: they were published from 2018 to 2023, they were original research comprising molecular, genetic and statistical data, and the data on verification of diagnosis; PTSD was to be the primary condition, the sampling being at least 60 patients.

FK50-BINDING PROTEIN GENE, FKBP5. CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 AND 2 GENES, CRHR1/2. ALPHA-5-NICOTINE CHOLINORECEPTOR GENE, CHRNA5. ROR-RELATED ORPHAN RECEPTOR ALPHA GENE, RORA

Zhang et al. (2020) studied the role of SNVs of several genes including FKBP5 (rs3800373, rs1360780, rs9470080 and rs9296158), CRHR1 (rs4458044 и rs242924) and CRHR2 (rs8192496 and rs2267715) in 1,132 patients with PTSD surviving earthquakes in China. They found that the minor allele A of the polymorphism rs2267715 in CRHR2 was associated with a more severe progress of PTSD (p<0.01, beta = 1.26, 95%CI = 0.41-2.11). Besides, they saw a statistically significant impact of the SNV FKBP5-CRHR1 (rs9470080 × rs4458044) on the severity of PTSD in men (p <0.05) [11] (Table 1). Boscarino et al. (2022) studied four genetic markers related to PTSD: FKBP5 (rs16969968), RORA (rs8042149), CRHR1 (rs110402), and CHRNA5 (rs16969968). They found that the link of the first two SNVs with the development of PTSD was statistically significant (p<0.05) [12]. Hu et al. (2020) reported similar results of the study with a different sampling [13].

In other studies, the groups of Zhang (2020) and Tamman (2019) studies the connections between the SNV of the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080) and the diagnosis of PTSD among veterans of military conflicts. They found that patients with PTSD manifested the alleles A SNV rs3800373, G SNV rs9296158, C SNV rs1360780 and C SNV rs9470080 (p<0.01) with higher frequency [11, 14]. Besides, Hu et al. (2020) showed that the people with two minor alleles FKBP5 (rs9296158, rs3800373, rs1360780 and rs9470080) subjected to physical violence in childhood showed higher severity of PTSD symptoms [13].

Li et al. (2019) studied four known SVNs of the FKBP5 gene (rs3800373, rs9296158, rs1360780 and rs9470080) on the sample of 1,140 adult patients with PTSD (Table 1). They found that the rs9470080 TT genotype was associated with the higher risk of development of PTSD and depression after low-severity stress events (p<0.05; OR = 0.13, 95%CI = 0.03-0.63) [15]. Young et al. (2018) did not find any connection between the development of PTSD and the interaction of rs1360780 and psychological traumatization in the childhood [16]. In the study performed on the sample of military veterans diagnosed with PTSD, Kang et al. (2019) studied the SNV rs1360780 and found no statistically significant differences between the groups [17]. Jaksic et al. (2019) reported credible associations between the C allele SNV rs1360780 of the FKBP5 gene and the diagnosis of PTSD, and the severity of symptoms of the dominant model. However, these connections failed to keep their statistical significance after the Bonferroni correction (á=0.002), as well as the connection of PTSD with SNV rs17689918 CRHR1 [18].

Gelernter et al. (2019) performed a search for the whole genome associations using a sample of 146,660 military service veterans and identified the most significant associations with PTSD symptoms (p<0.001): CRHR1 (allele С, rs1724402), CAMKV (rs2777888)KANSL1 (rs2532252) and TCF4 (rs2123392). Besides, the authors identified the statistically significant connections with other SNVs, including KCNIP4 (rs4697248), HSD17B11 (rs7688962), MAD1L1 (rs10235664), SRPK2 (rs67529088) and LINC01360 (rs7519147) [19].

ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE TYPE I RECEPTOR GENE, ADCYAP1R1. SODIUM-DEPENDENT SEROTONIN TRANSPORTER GENE, SLC6A4

In the work performed by the group of (2021), the connection of the SNV of the ADCYAP1R gene (rs2267735) with the development of PTSD was studied on the sample of 1,132 patients surviving an earthquake. The researchers found the statistically significant connection of interaction of ADCYAP1R1–FKBP5 (rs2267735 × rs1360780) with the severity of the clinical pattern of PTSD (beta = -1.31, p<0.05). Besides, there was identified the statistically significant connection of the interaction of ADCYAP1R1CRHR1 (rs2267735 × rs242924) with severity of PTSD in men (p<0.05) [20, 21].

Kravić et al. (2019) reported absence of significant connections of PTSD with the distribution of genotypes SLC6A4 (serotonin membrane transporter) and MAOA (responsible for serotonin metabolism) in the sample 719 patients with PTSD and conventionally healthy people surviving a military conflict [22]. Taylor et al. (2019) studied the connections between the impact of explosion, 5HTTLPR and PTSD symptoms. The people exposed to the explosion and having the S-allele had a more severe progression of PTSD as compared to carriers of the S-allele not exposed to the explosion, and to carriers of both LL alleles. (p<0.01) [23].

TYPE II AND IV DOPAMINE RECEPTOR GENE, DRD2/4. GLUCOCORTICOID RECEPTOR GENE, NR3C1

The study of Xiao et al. (2019) showed that the polymorphisms DRD2 Taq I and 5-HTTVNTR had statistically significant connection to the PTSD diagnosis, whereas the 5-HTTLPR had none. The genotype A1/A1 of the polymorphism DRD2 Taq1 had significant association with the increased risk of development of PTSD (OR = 2.39, 95%CI = 1.39-4.12, p<0.01). On the contrary, the genotype 10/10 5-HTTVNTR decreased the risk of PTSD development with statistical significance (OR = 0.17, 95%CI = 0.08-0.34, p<0.001) [24]. Yuan et al. (2022) studied the associations between the SNV rs1800497 (Taq1A), severity of PTSD and the volumes of the CA3 zone and the fascia dentata of the hippocampus. Even though they did not find any statistically significant association between the severity of PTSD and the total volume of the hippocampus in patients with the TT genotype, there was found a significant connection between the genotype and severity of PTSD, the most grave clinical pattern was related with reduction of the volume of the left CA3 among the TC heterozygotes (p<0.01) [25].

Hoxha et al. (2019) studied associations between the DRD2 variant (rs1800497) and the variable number of tandem repetitions (VNTR), located in the third exon DRD4 with the development of PTSD. The case control study found no significant associations. However, there was identified an association between SNV DRD2 (rs1800497) and deviations in the score of PTSC symptoms per “Brief Symptom Inventory” scale both in the genotype and recessive models, the allele T being the risk allele (p<0.05) [26].

The study of Zhang et al. (2018) genotypified the SNVs of three genes DRD2/ANNK1COMT and DBH in adults exposed to earthquake. The variant rs1800497 is related to the density of D2 dopamine receptors, and the haplotypes rs6269-rs4633-rs4818-rs4680 impact the level and the activity of the catechol-O-methyl transferase metabolizing catechol amines. The statistical analysis of genetic data identified interaction between DRD2/ANNK1-COMT (rs1800497 × rs6269) that was associated with the PTSD diagnosis. However, the analysis involving singular SNVs revealed no significance in the development of PTSD in any of them, as well as the ‘gene-environment’ interaction [27]. Furthermore, the same study of Zhang et al. (2019) analyzed two SNVs (rs2268498 in OXTR and rs1801028 in DRD2) in the Chinese cohort that was exposed to the earthquake in Wenchuan including 156 cases of PTSD and 978 people in the control group. The interaction between the genotypes rs2268498 CC/CT and the allele C SNV rs1801028 was associated with the PTSD diagnosis (p<0.01; OR = 9.18, 95%CI = 3.07 - 27.46) [28] (Table 1).

 

Table 1. Summary of the associations between common SNVs, gene interactions, haplotypes and PTSD

Таблица 1. Связи однонуклеотидных вариантов, межгенных взаимодействий и гаплотипов c риском развития ПТСР

Gene and localization of its expression

References

Cohort

Methods of assessment

Key findings

FKBP5 Hippocampus

Zhang et al. 2020

3890 people (18-62 years); М/F; All races; Military veterans

PCL-4

PTSD(+): A-allele of rs3800373 (p<0.001; OR=1.3, 95%CI 1.1-1.6), G-allele of rs9296158 (p<0.001; OR=0.2, 95%CI 0.2-0.3), the C-allele of rs1360780 (p<0.001; OR=1.3, 95%CI 1.1-1.6), the C-allele of rs9470080 (p=0.001; OR=2.9, 95%CI 2.4-3.4).

PTSD(+) often had AGCC haplotype (rs3800373-rs9296158-rs1360780-rs9470080) (p<0.01; ÷2=9.1) than PTSD(-).

Qi et al. 2020

237 people; М/F; Chinese; Child loss experience

CAPS SCID

The distribution of the AGCC haplotype (rs3800373-rs9296158-rs1360780-rs9470080) was found to be significantly higher in the probable PTSD group compared to the non-PTSD group.

Li et al. 2019

1140 people (17-66 years); М/F; Chinese; Earthquake Survivors

PCL-5

PTSD(+): T-allele (rs9470080) (p<0.05; OR = 0.1, 95%CI 0.03-0.6).

PTSD(+)-depression: AGCT haplotype (rs3800373-rs9296158-rs1360780-rs9470080).

No significance: rs3800373, rs9296158 and rs1360780.

Young et al. 2018

266 (18-62 years); М/F; All races; Military veterans

CAPS

PTSD(+): T-allele (rs1360780) (OR = 1.91, 95%CI 1.0-3.5).

Jaksic et al. 2019

719 people; М/F; Caucasian; War survivors

CAPS, BSI, M.I.N.I.

No significance: C-allele (rs1360780).

Kang et al. 2019

239 people; M; Military veterans

CAPS, PCL-4

PTSD(+): C-allele (dominant model) (rs1360780) (F=7.3; p<0.01).

Hu et al. 2020

1042 people; М/F; Caucasian; Military veterans

PCL-5

PTSD(+): C-allele (rs9470080) (p<0.05).

Tamman et al. 2019

577 people; М/F; Military veterans

PCL-5, SCID, CAPS

PTSD(+): G-allele (rs9296158), A-allele (rs3800373), C-allele (rs1360780), C-allele (rs9470080) (p≤0.001).

ADCYAP1R Amygdala and hippocampus

Wang et al. 2021

1132 people (18-73 years); М/F; Chinese; Earthquake Survivors

PCL-5

PTSD(+): ADCYAP1R1-FKBP5 (rs2267735 × rs1360780) associated with severity (beta = -1.3 and P = 0.05);

ADCYAP1R1-CRHR1 (rs2267735 × rs242924) correlated with severity in men (beta = -4.7 and P = 0.02).

DRD2, DRD4 Hippocampus

Yuan et al. 2022

142 people (18-60 years); М/F; Chinese; Earthquake Survivors

SCID, CAPS

PTSD(+): Severe - reduced left CA3 volume - TC heterozygotes (rs1800497) (p<0.01).

Hoxha et al. 2019

719 people; М/F; Caucasian; War survivors

CAPS, BSI

No significance: TaqI (rs1800497 of DRD2) and VNTR in exon 3 (DRD4).

Zhang et al. 2018

1134 people (16-73 years); М/F; Chinese; Earthquake Survivors

PCL-5

PTSD(+): DRDхANNK1-COMT (rs1800497×rs6269) (p<0.05).

No significance: DRD2 (rs1800497)

Zhang et al. 2019

1134 people (16-73 years); М/F; Chinese; Earthquake Survivors

PCL-5

PTSD(+): OXTR–DRD2 (rs2268498×rs1801028) (p<0.01; OR = 9.2, 95%CI 3.1-27.5).

CRHR1, CRHR2 Hypothalamus

Zhang et al. 2020

1132 people (18-73 years); М/F; Chinese; Earthquake Survivors

PCL-5

PTSD(+): CRHR2 A-allele (rs2267715) increased severity (p<0.01; beta = 1.3, 95%CI 0.4-2.1),

FKBP5-CRHR1 (rs9470080×rs4458044 and rs9296158 × rs4458044) was severity in men (p<0.05).

Boscarino et al. 2022

1074 people; М/F; Caucasian, Non-whites; Military veterans

PCL-5

PTSD(+): CRHR1 (G-allele; rs110402), CHRNA5, (A-allele; rs16969968), RORA (G-allele; rs8042149), FKBP5 (T-allele; rs16969968) (p<0.05).

Gelernter et al. 2019

146 660 people; М/F; All races; Military veterans

PCL-4

PTSD(+): CRHR1 С-allele (rs1724402) was associated with PTSD (p<0.001)

SLC6A4 Amygdala

Kravić et al. 2019

719 people; М/F; Caucasian; War survivors

CAPS, BSI

No significance: 5-HTTLPR (high-expressing long allele and low-expressing short allele)

Taylor et al. 2019

78 people; M; Blast exposure interacts

PCL-5

Homozygous S carriers of 5HTTLPR showed higher PTS rates than homozygous L carriers (p<0.01).

Xiao et al. 2019

4072 people (13-18 years); М/F; Chinese; Earthquake Survivors

PCL-4

PTSD(+): A1/A1 of Taq1A (rs1800497 of DRD2) (p<0.01; OR = 2.4, 95%CI 1.4-4.1),

PTSD(-): 10/10 of 5-HTTVNTR (p<0.001; OR = 0.166, 95%CI 0.1-0.3) No significance: 5-HTTLPR (short or long alleles)

NR3C1 Prefrontal cortex

Castro-Vale et al. 2021

61 people; М; Caucasian; Military veterans

CAPS, SCID

PTSD(+): G-allele (rs6198) (p=0.05; OR = 3.6, 95%CI 1.1-11.8).

No significance: rs10052957, rs6189/rs6190, rs6195, rs41423247.

Note: PTSD – Post-traumatic stress disorder; PTSD(+) – the group of findings, that showed significantly positive associations with PTSD expressiveness; PTSD(-) – the group of findings, that showed reverse associations with PTSD expressiveness; FKBP5 – FK506 binding protein 5; ADCYAP1R – adenylate cyclase activating polypeptide 1 (pituitary) receptor; DRD2, DRD4 – Dopamine receptor D2/4; CRHR1, CRHR2 – Corticotropin-releasing hormone receptor 1/2; SLC6A4 – Solute carrier family 6 member 4, aka 5-HTT Variants: 5HTTLPR & 5HTTVNTR; NR3C1 – Nuclear receptor subfamily 3, group C, member 1 aka GR; CAPS - Clinician Administrated PTSD Scale; BSI - the Brief Symptom Inventory; PCL-4/5 - PTSD CheckList 4/5, SCID - Structured Clinical Interview for DSM Disorders; M.I.N.I - Mini International Neuropsychiatric Interview.

Примечания: ПТСР – посттравматическое стрессовое расстройство; ПТСР(+) – группа данных, показавших достоверную положительную связь с выраженностью ПТСР; ПТСР(-) – группа данных, показавших обратную связь с выраженностью ПТСР; FKBP5 – ген FK506-связывающего белка; ADCYAP1R – ген рецептора к активатору аденилатциклазы 1; DRD2, DRD4 – гены рецепторов дофамина D2/4; CRHR1, CRHR2 – гены рецепторов кортикотропин-рилизинг-гормона 1/2; SLC6A4 – ген транспортера серотонина, также известный как 5-HTT: 5HTTLPR и 5HTTVNTR; NR3C1 – ген глюкокортикоидного рецептора; CAPS – шкала ПТСР, назначаемая клиницистом (Clinician Administrated PTSD Scale); BSI – Brief Symptom Inventory; PCL-4/5 – Контрольный список ПТСР 4/5; SCID – Структурированное клиническое интервью по расстройствам DSM; M.I.N.I - Мини-международное нейропсихиатрическое интервью.

 

Castro-Vale et al. (2021) studies the association between five SNVs of the gene NR3C1 (rs10052957, rs6189/rs6190, rs6195, rs41423247 and rs6198) and PTSD in veterans of colonial wars in Portugal. The carriership of the variant 9â (allele G) rs6198 showed the statistically significant association with PTSD within the dominant morel of heredity, and was associated with the severity of the clinical pattern of PTSD [29].

DISCUSSION

From the 20 studies in question, eight studied the SNVs of the glucocorticoid chaperon gene FKBP5, with the total sample of 8110 people. All authors studying the SNV FKBP5 reported significant associations with PTSD for the variant rs9470080, regardless of the allele, C or T. However, the results for other variants (rs9296158, rs3800373, rs1360780) were ambiguous or statistically insignificant [13–18, 30]. The associations between the two haplotypes (A-G-C-C и A-G-C-T) and the specifics of progression of PTSD are of special interest due to novelty of results, yet the current data is insufficient to make any firm conclusions [15, 30, 31]; same concerns the results for interactions between the FKBP5 and other genes [14, 20].

As far as the dopamine receptor genes DRD2/4 are concerned, four studies focused on their SNVs in a total sample of 1995 people and reported, mainly, insignificant associations with PTSD [25–28]. However, the group of Zhang (2018, 2019) found statistically significant interactions between DRD2/ANKK1-Taq1A-COMT (rs1800497 × rs6269) and OXTR–DRD2 (rs2268498 × rs1801028) in a sample of 1134 people (p<0.05) [25, 28]. These results, in their turn, need further research to support their significance.

Among other research, three studies of CRHR1/2 showed significant associations between separate SNVs and the development of PTSD [11, 12]. The study involving the genome-wide association search by Gelernter et al. (2019) on the sample of 146,660 military service veterans, the most significant association with PTSD was found for the C-allele CRHR1 (rs1724402) (p<0.001) [19]. At the same time, the high significance of associations with the development of PTSD was seen in other SNVs: CAMKV (rs2777888), KANSL1 (rs2532252) and TCF4 (rs2123392) (p<0.001). This additional data had lesser statistical significance as compared with the SNVs mentioned above, but it deserves attention in the light of further research [19]. Based on the comparison of results shown in Table 1, the authors consider discussion of remaining studies unpractical due to contradictory data.

Generally, the presented results show some role of the genes coding the component of the neuroendocrine axis in the etiology of PTSD and the contribution made therein by the neurotransmission of catechol amines and serotonin. The correction of discrepancy in data used for our research is a question of major scientific interest. It is necessary to study the SNVs of the FKBP5 gene, the haplotypes and the intergenic interactions, as well as earlier neglected SNVs showing high significance of connections with development of PTSD in genome-wide association study, which allows learning the epigenetic aspects of PTSD development, among other things [19, 32]. The answer to the question of the SNV contribution to the development of PTSD is vital for the targeted intervention that could only be performed immediately after the psychological trauma but before the progress of dysfunctions under PTSD would become stable with relevant morphofunctional changes in the patient’s brain [33].

CONCLUSIONS

The analysis of the selected papers revealed two highly significant genetic markers related to the development of PTSD: FKBP5 (rs9470080, both the C-allele and the T-allele) and the C-allele of CRHR1 (rs1724402). These results point at the hypothalamo-pituitary-adrenal axis and the neuroendocrine path as the potential target for the pre-clinical treatment in order to mitigate the risk and prevent the development of PTSD. Other results, such as the association of the haplotypes of FKBP5 (A-G-C-C: rs3800373-rs9296158-rs1360780-rs9470080A-G-C-T: rs3800373-rs9296158-rs1360780-rs9470080) and FKBP5-CRHR1 (rs9470080 × rs4458044 and rs9296158 × rs4458044) were less significant and studied in less detail. Collated data is of value to identify the vector of our future research. The authors think that genetic testing of patients exposed to psychological trauma might become the foundation for the primary prevention of PTSD in order to impede the cascade of changes in the nervous system leading to the sustainable clinical symptomatology. Although some singular genetic factors of PTSD development are well known, our understanding of the polygenic nature of the illness remains limited, considering insufficient data on epigenetic mechanisms of mental disorders. The priority studies of molecular and genetic foundations of PTSD can ensure a more detailed insight into the pathogenic mechanisms of the disease and development of efficient methods of its prevention and treatment. 

ADDITIONAL INFORMATION

Study limitations.

The study is subject to the typical limitations of review work. The present results are limited by the heterogeneous designs of the studies used for the analysis, as well as by the insufficient sample size to formulate unambiguous conclusions. We observe the need for further research clarifying the significance of risk factors for PTSD, taking into account the polygenic nature and epigenetic mechanisms of the disease.

Study funding. The article is the part of the "InPsyReSearch project: Priority 2030".

Conflict of Interest. The authors declare that there are no obvious or potential conflicts of interest associated with the content of this article.

Contribution of individual authors. T.S. Syunyakov, Х. Gonda, A.T. Sak, D.A. Smirnova – formulated the main idea and clarified the hypothesis; guided the study design; provided detailed manuscript editing. A.Ya. Gajduk, A.S. Sustretov, D.A. Kokorev, A.A. Kuznetsov – were responsible for scientific data collection, its systematization and analysis, wrote the first draft of the manuscript.

All authors gave their final approval of the manuscript for submission, and agreed to be accountable for all aspects of the work, implying proper study and resolution of issues related to the accuracy or integrity of any part of the work.

ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ

Ограничения исследования.

Исследование подвержено типичным ограничениям обзорной работы. Настоящие результаты ограничены гетерогенными дизайнами исследований, использованных для анализа, а также недостаточным объемом выборки для формулирования однозначных выводов. Мы видим необходимость дальнейших исследований, связанных с уточнением значимости факторов риска развития ПТСР, учитывая полигенную природу и эпигенетические механизмы заболевания.

Источник финансирования. Работа была проведена в рамках проекта «Банк инновационных нейропсихиатрических исследований: Приоритет-2030».

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с содержанием настоящей статьи.

Участие авторов. Т.С. Сюняков, К. Гонда, А.Т. Сак, Д.А. Смирнова – формулировка основной идеи и уточнение гипотезы; руководство оформлением исследования; редактирование рукописи. А.Я. Гайдук, А.С. Сустретов, Д.А. Кокорев, А.А. Кузнецов – сбор литературных данных, их систематизация и анализ, написание текста.

Все авторы одобрили финальную версию статьи перед публикацией, выразили согласие нести ответственность за все аспекты работы, подразумевающую надлежащее изучение и решение вопросов, связанных с точностью или добросовестностью любой части работы.

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About the authors

Arsenii Ya. Gayduk

Samara State Medical University; National Research Institute of Public Health and Healthcare Management

Email: a.j.gayduk@samsmu.ru
ORCID iD: 0000-0002-4015-3162

Head of the Youth Laboratory on Innovations in Neuropsychiatry, International Centre for Education and Research in Neuropsychiatry

Russian Federation, Samara; Moscow

Aleksei S. Sustretov

Samara State Medical University

Email: a.s.sustretov@samsmu.ru
ORCID iD: 0000-0002-3021-2130

Head of Laboratory of Human Metagenomics, Professional Center for Education and Research in Genetic and Laboratory Technologies

Russian Federation, Samara

Daniil A. Kokorev

Samara State Medical University

Email: d.a.kokorev@samsmu.ru
ORCID iD: 0000-0002-9991-6750

Specialist of Laboratory of Human Metagenomics, Professional Center for Education and Research in Genetic and Laboratory Technologies

Russian Federation, Samara

Aleksei A. Kuznetsov

Samara State Medical University

Email: talking.fish00@gmail.com
ORCID iD: 0009-0009-1737-6366

Assiatant, International Centre for Education and Research in Neuropsychiatry

Russian Federation, Samara

Xenia Gonda

Samara State Medical University; Semmelweis University

Email: kendermagos@yahoo.com
ORCID iD: 0000-0001-9015-4203

PhD, Professor, Department of Psychiatry and Psychotherapy

Russian Federation, Samara; Budapest, Hungary

Alexander T. Sack

Maastricht University

Email: a.sack@maastrichtuniversity.nl
ORCID iD: 0000-0002-1471-0885

PhD, Professor of School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences

Netherlands, Maastricht

Timur S. Syunyakov

Samara State Medical University; Republican Specialized Scientific and Practical Medical Center of Mental Health

Email: sjunja@gmail.com
ORCID iD: 0000-0002-4334-1601

PhD, Chief Specialist of the ICERN; Chief advisor on R&D

Russian Federation, Samara; Tashkent, Uzbekistan

Darya A. Smirnova

Samara State Medical University

Author for correspondence.
Email: d.a.smirnova@samsmu.ru
ORCID iD: 0000-0002-9591-4918
SPIN-code: 8248-0194

PhD, Director of the International Centre for Education and Research in Neuropsychiatry

Russian Federation, Samara

References

  1. Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. Trauma and PTSD in the WHO World Mental Health Surveys. Eur J Psychotraumatol. 2017;8(5):1353383. https://doi.org/10.1080/20008198.2017.1353383
  2. Yassa MA, Stark CE. Pattern separation in the hippocampus. Trends Neurosci. 2011;34(10):515-525. https://doi.org/10.1016/j.tins.2011.06.006
  3. Guzowski JF, Knierim JJ, Moser EI. Ensemble dynamics of hippocampal regions CA3 and CA1. Neuron. 2004;44(4):581-584. https://doi.org/10.1016/j.neuron.2004.11.003
  4. Fox AS, Kalin NH. A translational neuroscience approach to understanding the development of social anxiety disorder and its pathophysiology. Am J Psychiatry. 2014;171(11):1162-1173. https://doi.org/10.1176/appi.ajp.2014.14040449
  5. Dieter JN, Engel SD. Traumatic Brain Injury and Posttraumatic Stress Disorder: Comorbid Consequences of War. Neurosci Insights. 2019;14:1179069519892933. https://doi.org/10.1177/1179069519892933
  6. Quinones MM, Gallegos AM, Lin FV, Heffner K. Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: an integrative review. Cogn Affect Behav Neurosci. 2020;20(3):455-480. https://doi.org/10.3758/s13415-020-00782-9
  7. Ressler KJ, Berretta S, Bolshakov VY, et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol. 2022;18(5):273-288. https://doi.org/10.1038/s41582-022-00635-8
  8. Bromis K, Calem M, Reinders AATS, et al. Meta-Analysis of 89 Structural MRI Studies in Posttraumatic Stress Disorder and Comparison With Major Depressive Disorder. Am J Psychiatry. 2018 1;175(10):989-998. https://doi.org/10.1176/appi.ajp.2018.17111199
  9. Afifi TO, Asmundson GJ, Taylor S, Jang KL. The role of genes and environment on trauma exposure and posttraumatic stress disorder symptoms: a review of twin studies. Clin Psychol Rev. 2010;30(1):101-12. https://doi.org/10.1016/j.cpr.2009.10.002
  10. Zhang K, Qu S, Chang S, et al. An overview of posttraumatic stress disorder genetic studies by analyzing and integrating genetic data into genetic database PTSDgene. Neurosci Biobehav Rev. 2017;83:647-656. https://doi.org/10.1016/j.neubiorev.2017.08.021
  11. Zhang L, Hu XZ, Yu T, et al. Genetic association of FKBP5 with PTSD in US service members deployed to Iraq and Afghanistan. J Psychiatr Res. 2020;122:48-53. https://doi.org/10.1016/j.jpsychires.2019.12.014
  12. Boscarino JA, Adams RE, Urosevich TG, et al. Genetic and Psychosocial Risk Factors Associated with Suicide Among Community Veterans: Implications for Screening, Treatment and Precision Medicine. Pharmgenomics Pers Med. 2022;14;15:17-27. https://doi.org/10.2147/PGPM.S338244
  13. Hu Y, Chu X, Urosevich TG, et al. Predictors of Current DSM-5 PTSD Diagnosis and Symptom Severity Among Deployed Veterans: Significance of Predisposition, Stress Exposure, and Genetics. Neuropsychiatr Dis Treat. 2020;16:43-54. https://doi.org/10.2147/NDT.S228802
  14. Tamman AJF, Sippel LM, Han S, et al. Attachment style moderates effects of FKBP5 polymorphisms and childhood abuse on post-traumatic stress symptoms: Results from the National Health and Resilience in Veterans Study. World J Biol Psychiatry. 2019;20(4):289-300. https://doi.org/10.1080/15622975.2017.1376114
  15. Li G, Wang L, Zhang K, et al. FKBP5 Genotype Linked to Combined PTSD-Depression Symptom in Chinese Earthquake Survivors. Can J Psychiatry. 2019;64(12):863-871. https://doi.org/10.1177/0706743719870505
  16. Young DA, Inslicht SS, Metzler TJ, et al. The effects of early trauma and the FKBP5 gene on PTSD and the HPA axis in a clinical sample of Gulf War veterans. Psychiatry Res. 2018;270:961-966. https://doi.org/10.1016/j.psychres.2018.03.037
  17. Kang JI, Kim TY, Choi JH, et al. Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder. Psychoneuroendocrinology 2019;103: 1-7. https://doi.org/10.1016/j.psyneuen.2018.12.226
  18. Jaksic N, Šabić Džananović E, Aukst Margetic B, et al. A Candidate Gene Association Study of FKBP5 and CRHR1 Polymorphisms in Relation to War-Related Posttraumatic Stress Disorder. Psychiatr Danub. 2019;31(2):269-275. https://doi.org/10.24869/psyd.2019.269
  19. Gelernter J, Sun N, Polimanti R, et al. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat Neurosci. 2019;22(9):1394-1401. https://doi.org/10.1038/s41593-019-0447-7
  20. Wang L, Zhang J, Li G, et al. The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population. Front Psychiatry. 2021;7;12:665599. https://doi.org/10.3389/fpsyt.2021.665599
  21. Zhang J, Li G, Yang H, Cao C, et al. The main effect and gene-environment interaction effect of the ADCYAP1R1 polymorphism rs2267735 on the course of posttraumatic stress disorder symptoms-A longitudinal analysis. Front Psychiatry. 2022;13:1032837. https://doi.org/10.3389/fpsyt.2022.1032837
  22. Kravić N, Šabić Džananović E, Muminović Umihanić M, et al. Association Analysis of Maoa and Slc6a4 Gene Variation in South East European War Related Posttraumatic Stress Disorder. Psychiatr Danub. 2019;31(2):211-218. https://doi.org/10.24869/psyd.2019.211
  23. Taylor MK, Hernández LM, Stump J, et al. Blast exposure interacts with genetic variant 5HTTLPR to predict posttraumatic stress symptoms in military explosives personnel. Psychiatry Res. 2019; 280:112519. https://doi.org/10.1016/j.psychres.2019.112519
  24. Xiao Y, Liu D, Liu K, et al. Association of DRD2, 5-HTTLPR, and 5-HTTVNTR Gene Polymorphisms With Posttraumatic Stress Disorder in Tibetan Adolescents: A Case-Control Study. Biol Res Nurs. 2019;21(3):286-295. https://doi.org/10.1177/1099800419838325
  25. Yuan M, Zhu H, Li Y, et al. The DRD2 Taq1A polymorphism moderates the effect of PTSD symptom severity on the left hippocampal CA3 volume: a pilot study. Psychopharmacology (Berl). 2022; 239(11):3431-3438. https://doi.org/10.1007/s00213-021-05882-z
  26. Hoxha B, Goçi Uka A, Agani F, et al. The Role of TaqI DRD2 (rs1800497) and DRD4 VNTR Polymorphisms in Posttraumatic Stress Disorder (PTSD). Psychiatr Danub. 2019;31(2):263-268. https://doi.org/10.24869/psyd.2019.263
  27. Zhang K, Wang L, Cao C, et al. A DRD2/ANNK1-COMT Interaction, Consisting of Functional Variants, Confers Risk of Post-traumatic Stress Disorder in Traumatized Chinese. Front Psychiatry. 2018;9:170. https://doi.org/10.3389/fpsyt.2018.00170
  28. Zhang K, Li G, Wang L, et al. An epistasis between dopaminergic and oxytocinergic systems confers risk of post-traumatic stress disorder in a traumatized Chinese cohort. Sci Rep. 2019;9(1):19252. https://doi.org/10.1038/s41598-019-55936-8
  29. Castro-Vale I, Durães C, van Rossum EFC, et al. The Glucocorticoid Receptor Gene (NR3C1) 9β SNP Is Associated with Posttraumatic Stress Disorder. Healthcare (Basel). 2021;9(2):173. https://doi.org/10.3390/healthcare9020173
  30. Zhang K, Wang L, Li G, et al. Correlation between hypothalamic-pituitary-adrenal axis gene polymorphisms and posttraumatic stress disorder symptoms. Horm Behav. 2020;117:104604. https://doi.org/10.1016/j.yhbeh.2019.104604
  31. Qi R, Luo Y, Zhang L, et al. FKBP5 haplotypes and PTSD modulate the resting-state brain activity in Han Chinese adults who lost their only child. Transl Psychiatry. 2020;10(1):91. https://doi.org/10.1038/s41398-020-0770-5
  32. Swart PC, Du Plessis M, Rust C, et al. Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort. J Neurochem. 2023;166(4):705-719. https://doi.org/10.1111/jnc.15919
  33. Pape JC, Carrillo-Roa T, Rothbaum BO, et al. DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder. Clin Epigenetics. 2018;10(1):136. https://doi.org/10.1186/s13148-018-0569-x

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Copyright (c) 2024 Gayduk A.Y., Sustretov A.S., Kokorev D.A., Kuznetsov A.A., Gonda X., Sack A.T., Syunyakov T.S., Smirnova D.A.

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