Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder (DSM-V code: 309.81; ICD-10 codes: F43.1). PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically or/and psychologically distressing event. Its incidence and the number of this disease-affected people are threateningly increasing in contemporary society. Therefore, the development of prognostic strategies and novel efficient methods on early diagnostics and treatment of PTSD is currently considered as one of the most important healthcare problems worldwide.
Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Armenia
Avetyan Diana
Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Armenia
Hovhannisyan Lilit
Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Armenia
Mkrtchyan Gohar*
Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Armenia
*Address all correspondence to: g_mkrtchyan@mb.sci.am
1. Introduction
Posttraumatic stress disorder (PTSD; DSM-V code: 309.81; ICD-10 codes: F43.1) is a complex, severe, and chronic psychiatric illness [1–2]. PTSD is an anxiety disorder developed in a person experiencing, witnessing, or learning about an extreme physically and/or psychologically distressing event [3–7]. Its incidence and the number of disease-affected people are threateningly increasing in contemporary society. They usually remain out of society, become drug addicted, alcoholic, and often commit suicide [8–10]. Therefore, development of prognostic strategies, novel efficient methods on early diagnostics and treatment of PTSD is currently considered as one of the most important health care problems worldwide.
Results of epidemiologic, clinical, and experimental studies suggest implication of both environmental and genetic factors in pathomechanisms of PTSD, and that, most probably, PTSD belongs to the complex disorders with polygenic inheritance. PTSD is also unique in its exposure to an environmental (traumatic) event as the first criterion for diagnosis. Whereas the environmental factors triggering PTSD are well defined, less is known about PTSD-associated genetic variations and molecular etiopathomechanisms [11–17]. Although it is beyond the scope of many studies to comprehensively discuss the genetics of PTSD, it should be noted that there is an emerging literature on genetic variations in those neurobiological systems which drive responses to trauma and, consequently, are risk factors to develop PTSD. Many studies on detection of candidate genes association with PTSD are being carried up to date [18–26].
In the present chapter, we provide overview and discussion of the existing data, including genetic variants of serotonergic and dopaminergic systems, hypothalamic–pituitary–adrenal (HPA) axis, and other genes related to neurotransmission, neuromodulation, and stress physiology. Here, we have also included our own results on variations in genes encoding neuro, immune, and apoptotic mediators and regulators, and related transcription factors in PTSD patients. Potential role of these genetic variations in generation and development of PTSD is considered and the implication of relevant candidate genes in mechanisms responsible for disease progression is proposed.
Many studies indicate association between PTSD and polymorphisms of number of genes, suggesting a polygenic nature of PTSD. Several studies indicate that functional abnormalities in neuroendocrine system detected in PTSD patients are conditioned with hereditary factor [21–26]. Thus, as it follows from Table 1, PTSD is associated with the genetic mutations in a number of genes encoding neurotransmitters, hormones and their enzymes, hormone receptors and transporters.
Dopaminergic system dysregulation has long been implicated in the pathophysiology of PTSD. A positive association between the risk for development of PTSD and Taq1A (rs1800497) polymorphism of the dopamine D2 receptor gene was found [24–30]. The dopamine D3 receptor (DRD3) gene's 4 SNPs (rs2134655, rs201252087, rs4646996, and rs9868039) showed evidence of association with PTSD [31]. Also, positive association was revealed between tandem repeat polymorphism of dopamine transporter gene and PTSD, as well as between dopamine D4 transporter gene long allele and severity of PTSD symptoms [32]. Recent publications reported that carriers of the 9R of allele of the gene, encoding the dopamine transporter (SLC6A3, DAT, or DAT1), had increased the risk of PTSD [33–36]. This finding suggests that genetically determined features of DAT may contribute to the development of PTSD among trauma survivors. Genetic variants in dopamine beta-hydroxylase (DBH) gene represent a likely candidate for examining genetic contributions to PTSD because of the role this enzyme plays in converting dopamine to norepinephrine as a part of catecholamine synthesis [37, 38]. A significant association between one or more copies of the rs4680 allele of COMT and PTSD has been reported. Thus, regulation of COMT and subsequent catecholamine neurotransmitter cascades may be an important factor in fear processing for those with PTSD and similar psychiatric disorders [39, 40]. Moreover, a recent study has shown a significant association of the COMT allele rs4633C with total PTSD, and severity scores of D category (negative alterations in cognitions and mood) of DSM-V categories [41].
2.1.2. Serotonergic system candidate genes
Dysregulation of brain serotonergic systems has been implicated in the pathophysiology of PTSD; indeed, this pathway represents the most studied candidate in PTSD. The most studied polymorphism in this system is located in the promoter region of the serotonin transporter encoding gene (SLC6A4, 5-HTTLPR). Several studies indicated that this risk was associated with rs4795541, rs25531 genotypes, and PTSD [35, 42–45]. Serotonin receptor 2A rs6311 polymorphism has also been found to be associated with PTSD [46–47].
Goenjian and colleagues' studies have suggested association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms [48]. It was shown that the TPH-2 allele rs11178997T and COMT allele rs4633C together accounted for 7% of the variance in severity scores of PTSD. Carriers of these COMT and TPH-2 alleles may be at increased risk for PTSD. These findings provided biological support for dividing DSM-IV category C symptoms into DSM-V categories C and D [41].
2.1.3. GABAergic system
Inhibitory neurotransmitter, gamma-aminobutyric acid receptor gene (GABAA) has been studied in relation to PTSD. Three polymorphisms in the GABAA receptor subunit alpha 2 (GABRA2) had significant interactions with childhood trauma to predict PTSD [49].
2.1.4. HPA axis candidate genes
PTSD is also characterized by dysfunction of the stress response system, such that activity of the HPA axis is altered. Recent studies reported associations between PTSD and cannabinoid receptor (CNR1) gene variants NM_016083 and NM_033181; [50], glucocorticoid receptor (NR3C1, rs41423247, and rs258747) gene [51, 52], and between SNP in corticotropin-releasing hormone receptor-1 (CRHR1, rs12944712) and PTSD [53]. Also neuropeptide pituitary adenylate cyclase-activating polypeptide is regulating the stress response. Recently, a genetic variant in the PAC1 receptor (ADCYAP1R1; rs2267735) was found to be associated with PTSD [54, 55]. Of particular interest were the findings that a genetic variation of the glucocorticoid receptor cochaperone protein, FKBP5, moderates risk of developing PTSD in childhood abuse cases [56–61]. Binder and colleagues found that 4 SNPs in FKBP5 (rs9296158, rs3800373, 1360780, rs9470080) interacted with child abuse severity to predict adult PTSD symptoms [62].
2.1.5. Neurotrophic factor candidate genes
Brain derived neurotrophic factor (BDNF) is involved in the neural plasticity underlying the extinction of fear and recovery from stress, both disrupted in PTSD. Based on its role in hippocampal-dependent learning and the neurobiology of anxiety and depression, the BDNF gene has been studied in relation to PTSD. A significant interaction between DRD2 Taq1A (rs1800497) and Val66Met (rs6265) predicts PTSD severity [30]. Interestingly, a recent study in humans and rats suggested that BDNF overexpression may be a critical stress response underlying PTSD by showing that the Val66Met allele confers vulnerability to PTSD via startle data and plasma BDNF levels [63–66].
2.1.6. Other candidate genes
Apolipoprotein E (ApoE) is involved in stress dysregulation. A significant association between the ApoE2 allele and impaired memory and greater re-experiencing symptoms has been found in combat-exposed PTSD patients [67–69]. The monoamine oxidase B gene (MAOB) rs1799836 polymorphism has been studied in relation with PTSD because MAOB expression in platelets has been implicated in several psychopathologies and may represent a biomarker for vulnerability to psychiatric illness [70]. Recent studies of the link between neuropeptide Y (NPY) and PTSD were published [71]. However, another study did not find any association between polymorphism in NPY (Leu7Pro; rs16139) and PTSD in a population of Caucasian combat veterans [72]. Nievergelt and colleagues found evidence for phosphoribosyl transferase domain-containing protein 1 (PRTFDC1) as a potential novel PTSD gene, but this finding needs further replication [73]. Finally, it was reported that the regulator of G-protein signaling 2 (RGS2) belongs to a protein family that has been widely involved in neural plasticity, particularly associated with learning and memory, and may play a critical role in PTSD-associated cognitive dysfunction. In PTSD patients experiencing high stress and low social support, an association with RGS2 (rs4606) was found [74].
2.2. Complement system candidate genes
The complement system is major effector of the immune response, which acts on the interface of innate and adaptive immunity, and is a key component and trigger of many immunoregulatory mechanisms. Changes in the functional activity of the complement cascade contribute to the pathology of many human diseases [75–77], including mental disorders [78–83], and are also detected during physiological stress [84, 85]. It has already been demonstrated that complement system alterations are involved in PTSD pathogeneses, particularly hypoactivation state of the complement alternative pathway in PTSD patients, which positively and significantly correlates (p < 0.05) with total (frequency and intensity) PTSD symptom cluster of re-experiencing, avoidance, and hyperarousal, and with PTSD total symptom score [13]. Now, our interest is focused on studying the genetic basis of complement system regulators, particularly the role and genetic variants of complement factors B, H, and I (CFB, CFH, and CFI, accordingly) in PTSD. The distributions of genotypes for CFB, CFH, and CFI SNPs in both patients and control groups were in compliance with Hardy–Weinberg equilibrium (p > 0.05). The allele and phenotype frequencies of CFB, CFH, and CFI genetic variants in the groups of PTSD patients and controls are shown in Table 2.
Gene (SNP)
Genotypes
Alleles
Carriage
CFB rs12614
CC
CT
TT
C
T
T
PTSD
87 (0.58)
59 (0.4)
3 (0.02)
233 (0.78)
65 (0.22)
62 (0.42)
Controls
125 (0.55)
89 (0.4)
12 (0.05)
339 (0.75)
113 (0.25)
101 (0.45)
p
0.32
0.56
OR
0.84
1.13
95% CI:
0.59-1.19
0.75-1.72
CFB rs1048709
GG
GA
AA
G
A
A
PTSD
134 (0.918)
11 (0.075)
1 (0.007)
279 (0.955)
13 (0.045)
12 (0.08)
Controls
167 (0.92)
14 (0.08)
0 (0)
348 (0.96)
14 (0.04)
14 (0.08)
p
0.7
0.87
OR
1.16
0.94
95% CI:
0.54-2.50
0.42-2.09
CFH rs424535
TT
TA
AA
T
A
A
PTSD
56 (0.38)
47 (0.32)
44 (0.3)
159 (0.54)
135 (0.46)
91 (0.62)
Controls
74 (0.344)
108 (0.502)
33 (0.154)
256 (0.6)
174 (0.4)
141 (0.6)
p
0.145
0.47
OR
1.25
1.17
95% CI:
0.93-1.69
0.76-1.81
CFHrs1061170
CC
CT
TT
C
T
T
PTSD
30 (0.21)
53 (0.36)
63 (0.43)
113 (0.39)
179 (0.61)
83 (0.47)
Controls
24 (0.11)
104 (0.46)
97 (0.43)
152 (0.34)
298 (0.66)
128 (0.57)
p
0.17
1.0
OR
0.81
1.92
95% CI:
0.60-1.10
1.05-3.52
CFH rs800292
CC
CT
TT
C
T
T
PTSD
117 (0.8)
25 (0.17)
4 (0.03)
259 (0.89)
33 (0.11)
29 (0.2)
Controls
166 (0.74)
55 (0.24)
4 (0.02)
387 (0.86)
63 (0.14)
59 (0.26)
p
0.29
0.16
OR
0.78
1.43
95% CI:
0.50-1.23
0.87- 2.37
CFI rs10033900
TT
TC
CC
T
C
C
PTSD
38 (0.3)
62 (0.4)
49 (0.3)
138 (0.46)
160 (0.54)
111 (0.75)
Controls
69 (0.31)
99 (0.44)
57 (0.25)
237 (0.53)
213 (0.47)
156 (0.69)
p
0.089
0.279
OR
1.29
0.77
95% CI:
0.962-1.73
0.486-1.23
CFIrs1000954
GG
GA
AA
G
A
A
PTSD
98 (0.66)
40 (0.27)
10 (0.07)
236 (0.8)
60 (0.2)
50 (0.34)
Controls
84 (0.488)
75 (0.436)
12 (0.076)
243 (0.71)
101 (0.29)
87 (0.51)
p
0.02a
0.006b
OR
0.61
2.03
95% CI:
0.42-0.88
1.29-3.2
CFI rs4469075
CC
CG
GG
C
G
G
PTSD
19 (0.13)
60 (0.42)
65 (0.45)
98 (0.34)
190 (0.66)
79 (0.55)
Controls
17 (0.1)
76 (0.5)
71 (0.4)
110 (0.3)
218 (0.7)
93 (0.57)
p
1.0
0.75
OR
0.98
1.32
95% CI:
0.7-1.37
0.64– 2.70
Table 2.
Distribution of genotypes, alleles and carriage of minor alleles of CFB, CFH and CFI polymorphisms in patients with PTSD and controls.
apcorrected values for comparison of mutant allele frequency between PTSD patients and controls.
bpcorrected values for comparison of mutant allele carriage between PTSD patients and controls.
According to the results obtained, the CFI rs1000954*A allele was more frequent in controls than in patients (0.29 vs. 0.20, pnominal = 0.008, OR = 0.61, 95 %CI: 0.42-0.88). Also, the carriers of this allele were overrepresented in the group of controls compared to patients (0.51 vs. 0.34, pnominal = 0.002, OR = 2.03, 95% CI: 1.29–3.2). In case of other selected polymorphisms, no significant association with PTSD was found (p > 0.05).
2.3. Candidate genes of apoptosis
Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli [86]. According to various apoptotic stimuli, apoptosis can be induced by two major pathways: the intrinsic pathway (mitochondria-dependent pathway) and the extrinsic pathway (death receptor-dependent pathway) [87]. Recent studies reported that neuronal apoptosis of amygdala, hippocampus, and medial prefrontal cortex (mPFC) have a certain relationship with the pathogenesis of PTSD [88]. However, the role of apoptosis in the pathogenesis of PTSD is not yet entirely clear.
Apoptosis is the process of strict control multigene, known in the process of apoptosis with a series of apoptosis-related genes, such as Bcl-2 family, caspase family, C-myc oncogenes, and tumor suppressor gene P53, etc. The Bcl-2 family proteins play a crucial role in the process of apoptosis and are considered to be the final passage of apoptosis. Bcl-2 family proteins regulate mitochondrial structure and functional stability with the help of other apoptosis protein synergy. According to the recent study, the increase of the Bcl-2 and Bax expression and the imbalance in the Bcl-2/Bax ratio were few of the mechanisms causing mPFC neuronal apoptosis, which may be one of the reasons of PTSD development in rat [88].
According to our study, the rs956572*A minor allele of the BCL2 gene was overrepresented in patients with PTSD compared to healthy subjects (0.64 vs. 0.41, pnominal = 6.02E-11, OR = 2.59, 95% CI: 1.94–3.44). In addition, the carriers of this allele were more in the group of patients compared to controls (0.87 vs. 0.65, pnominal = 4.11E-7, OR = 3.53, 95% CI: 2.14–5.81). Further, we found that the rs1801018*G minor allele of the BCL2 gene was more frequent among controls compared to patients (0.5 vs. 0.4, pnominal = 0.0036, OR = 0.66, 95% CI: 0.50–0.87). Also, the carriers of the rs1801018*G minor allele were more frequent in controls than in patients (0.79 vs. 0.61, pnominal = 8.6E-5, OR = 2.41, 95% CI: 1.54–3.75). After Bonferroni correction, difference in allele frequency between the patient and the control groups minor alleles remained significant (Table 3).
Gene (SNP)
Genotypes
Alleles
Carriage
ANXA5 rs11575945
CC
CT
TT
C
T
T
PTSD
63 (0.79)
14 (0.17)
3 (0.04)
140 (0.875)
20 (0.125)
17 (0.21)
Controls
53 (0.71)
21 (0.28)
1 (0.01)
127 (0.85)
23 (0.15)
22 (0.29)
p
1.4a
0.75b
OR
0.79
0.65
95% CI:
0.41 - 1.5
0.31 - 1.35
ANXA11 rs1049550
GG
GA
AA
G
A
A
PTSD
83 (0.415)
101 (0.505)
16 (0.08)
267 (0.67)
133 (0.33)
117 (0.59)
Controls
68 (0.34)
97 (0.485)
35 (0.175)
233 (0.58)
167 (0.42)
132 (0.66)
p
0.013a
0.12b
OR
0.695
1.38
95% CI:
0.52 - 0.93
0.92 - 2.07
BCL2 rs956572
GG
GA
AA
G
A
A
PTSD
27 (0.135)
89 (0.445)
84 (0.42)
143 (0.36)
257 (0.64)
173 (0.87)
Controls
71 (0.355)
94 (0.47)
35 (0.175)
236 (0.59)
164 (0.41)
129 (0.65)
p
1.20E-10a
8.22E-07b
OR
2.59
3.53
95% CI:
1.94 - 3.44
2.14 - 5.81
BCL2 rs1801018
AA
AG
GG
A
G
G
PTSD
78 (0.39)
83 (0.415)
39 (0.195)
239 (0.6)
161 (0.4)
122 (0.61)
Controls
42 (0.21)
114 (0.57)
44 (0.22)
198 (0.5)
202 (0.5)
158 (0.79)
p
0.0072a
0.00017b
OR
0.66
2.41
95% CI:
0.5 - 0.87
1.54 - 3.75
Table 3.
Distribution of genotypes, alleles and carriage of minor alleles of ANXA5, ANXA11 and BCL2 polymorphisms in patients with PTSD and controls.
apcorrected values for comparison of mutant allele frequency between PTSD patients and controls.
bpcorrected values for comparison of mutant allele carriage between PTSD patients and controls.
The externalization of phosphatidylserine is one of the leading indicators of apoptosis. The annexins are multigene family of Ca2+-regulated phospholipid-dependent and membrane-binding annexin proteins [89]. One member of the annexin gene family, annexin A5, is known as a Ca2+-dependent, phospholipid-binding protein that inhibits protein kinase C (PKC) signaling. Although annexin A5 has been used for the detection of apoptosis, it shows high affinity for surface-exposed phosphatidylserine during apoptosis and may directly involve in apoptotic pathway [90]. Another member of annexins family is annexin A11, which is involved in calcium signaling, apoptosis, vesicle trafficking, cell growth, and the terminal phase of cell division [91].
According to the results obtained, the blood level of annexin-А5 was significantly lower in PTSD and which may also be one of the factors responsible for development of PTSD-associated low-grade inflammation [92, 93]. The results of annexin family proteins encoding genes association with PTSD are shown in Table 3. The ANXA11 gene rs1049550*A allele was more frequent among controls than in patients (0.42 vs. 0.33, pnominal = 0.013, OR = 0.695, 95% CI: 0.52–0.93). There were no significant differences of carriers of rs1049550*A minor allele in the group of patients compared to controls.
2.4. Candidate genes of synaptic plasticity
Synaptic plasticity change, which is a fundamental characteristic of the nervous system, underlies numerous aspects of cognition. Plasticity is essential for the recovery of the nervous system after injury, stroke, and other pathological processes and can permit remarkable functional recovery even after devastating damage, especially in a young and otherwise healthy brain. However, the very mechanisms of plasticity that permit development, learning, resilience, memory, and recovery can also contribute to behavioral dysfunction and to psychopathology [94].
Complexins are small, cytosolic proteins that bind to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex to regulate synaptic vesicle exocytosis. Complexin 1 and 2 are the two major isoforms in the brain [95, 96]. Significant alterations of complexins 2 expression levels are seen in a number of neurological and psychiatric disorders, including bipolar disorder [97–99], major depression [98, 100], Huntington's disease (HD) [101, 102], schizophrenia [97, 100, 103–107], Parkinson's disease [108], Alzheimer's disease [109], and PTSD [93].
Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and its receptor (NGFR) are the essential mediators of synaptic and morphological plasticity, neuronal growth, survival, and differentiation; especially in the developing brain, thought may play an important role in pathogenesis of PTSD. [110]
We have reviewed data related neurotransmitter/neuroendocrine systems that are known to be involved in the pathophysiology of PTSD and that may contribute to the symptoms and cognitive dysfunctions in these patients. In Table 4, we have collected our data concerning candidate genes of the proteins involved in synaptic plasticity which may contribute to PTSD.
Gene (SNP)
Genotypes
Alleles
Carriage
BDNF rs6265
GG
GA
AA
G
A
A
PTSD
150 (0.75)
48 (0.24)
2 (0.01)
348 (0.87)
52 (0.13)
50 (0.25)
Controls
129 (0.645)
67 (0.335)
4 (0.02)
325 (0.81)
75 (0.19)
71 (0.36)
p
0.03a
0.02b
OR
0.65
1.65
95% CI:
0.44 - 0.95
1.07 - 2.54
CPLX2 rs1366116
CC
CT
TT
C
T
T
PTSD
34 (0.39)
36 (0.41)
17 (0.2)
104 (0.6)
70 (0.4)
53 (0.61)
Controls
45 (0.6)
24 (0.32)
6 (0.08)
114 (0.76)
36 (0.24)
30 (0.4)
p
0.006a
0.02b
OR
2.2
0.43
95% CI:
1.4 – 3.6
0.2 - 0.8
CPLX2 rs3892909
CC
CT
TT
C
T
T
PTSD
16 (0.18)
45 (0.52)
26 (0.3)
77 (0.44)
97 (0.56)
71 (0.82)
Controls
15 (0.2)
41 (0.55)
19 (0.25)
71 (0.47)
79 (0.53)
60 (0.8)
p
1.7a
2.4b
OR
1.13
0.9
95% CI:
0.73 – 1.76
0.4 – 1.97
NTNG1 rs628117
AA
AG
GG
A
G
G
PTSD
47 (0.36)
66 (0.5)
19 (0.14)
160 (0.6)
104 (0.4)
85 (0.64)
Controls
36 (0.34)
43 (0.41)
26 (0.25)
115 (0.55)
95 (0.45)
69 (0.66)
p
0.2a
0.8b
OR
0.79
1.06
95% CI:
0.55 – 1.14
0.62 - 1.82
NGF rs6330
CC
CT
TT
C
T
T
PTSD
66 (0.33)
106 (0.53)
28 (0.14)
238 (0.6)
162 (0.4)
134 (0.67)
Controls
130 (0.65)
58 (0.29)
12 (0.06)
318 (0.8)
82 (0.2)
70 (0.35)
p
2.04E-09a
4.20E-10b
OR
2.64
3.77
95% CI:
1.9 - 3.6
2.5 - 5.7
NGF rs4839435
GG
GA
AA
G
A
A
PTSD
130 (0.65)
66 (0.33)
4 (0.02)
326 (0.8)
74 (0.2)
70 (0.35)
Controls
85 (0.425)
97 (0.485)
18 (0.09)
267 (0.67)
133 (0.33)
115 (0.58)
p
4.00E-06a
1.20E-05b
OR
0.46
0.4
95% CI:
0.33 - 0.63
0.27 - 0.6
NGFR rs11466155
CC
CT
TT
C
T
T
PTSD
109 (0.545)
82 (0.41)
9 (0.045)
300 (0.75)
100 (0.25)
91 (0.46)
Controls
110 (0.55)
75 (0.375)
15 (0.075)
295 (0.74)
105 (0.26)
90 (0.45)
p
1.37a
2b
OR
0.94
0.98
95% CI:
0.68 - 1.29
0.66 - 1.45
NGFR rs734194
CC
CT
TT
C
T
T
PTSD
164 (0.82)
34 (0.17)
2 (0.01)
362 (0.9)
38 (0.1)
36 (0.18)
Controls
109 (0.545)
74 (0.37)
17 (0.085)
292 (0.73)
108 (0.27)
91 (0.46)
p
2.74E-10a
8.82E-09b
OR
0.284
0.263
95% CI:
0.19 - 0.42
0.17 - 0.42
CHN1 rs14228
CC
CT
TT
C
T
T
PTSD
79 (0.395)
86 (0.43)
35 (0.175)
244 (0.61)
156 (0.39)
121 (0.6)
Controls
82 (0.41)
62 (0.31)
56 (0.28)
226 (0.565)
174 (0.435)
118 (0.59)
p
0.39a
1.52b
OR
0.83
0.94
95% CI:
0.63 - 1.1
0.63 - 1.4
CHN1 rs2646153
AA
AG
GG
A
G
G
PTSD
50 (0.25)
86 (0.43)
64 (0.32)
186 (0.465)
214 (0.535)
150 (0.75)
Controls
57 (0.285)
90 (0.45)
53 (0.265)
204 (0.51)
196 (0.49)
143 (0.72)
p
0.4a
0.86b
OR
1.2
0.84
95% CI:
0.9 - 1.6
0.54 – 1.3
FOS rs7101
CC
CT
TT
C
T
T
PTSD
12 (0.06)
71 (0.355)
117 (0.585)
95 (0.24)
305 (0.76)
188 (0.94)
Controls
94 (0.47)
85 (0.43)
21 (0.1)
273 (0.68)
127 (0.31)
106 (0.53)
p
4.04E-37a
1.31E-21b
OR
6.9
13.9
95% CI:
5.1 - 9.4
7.3 - 26.5
FOS rs1063169
GG
GT
TT
G
T
T
PTSD
161 (0.8)
36 (0.18)
3 (0.02)
358 (0.9)
42 (0.1)
39 (0.2)
Controls
92 (0.46)
80 (0.4)
28 (0.14)
264 (0.66)
136 (0.34)
108 (0.54)
p
1.50E-15a
1.70E-12b
OR
0.23
0.21
95% CI:
0.16 - 0.33
0.13 - 0.32
JUN rs11688
GG
GA
AA
G
A
A
PTSD
34 (0.17)
113 (0.565)
53 (0.265)
181 (0.45)
219 (0.55)
166 (0.83)
Controls
47 (0.24)
111 (0.56)
42 (0.2)
205 (0.51)
195 (0.49)
153 (0.77)
p
0.09a
0.11b
OR
1.27
0.67
95% CI:
0.96 - 1.68
0.4 - 1.1
IER5 rs6425663
GG
GT
TT
G
T
T
PTSD
29 (0.145)
78 (0.39)
93 (0.465)
136 (0.34)
264 (0.66)
171 (0.86)
Controls
20 (0.1)
74 (0.37)
106 (0.53)
114 (0.285)
286 (0.715)
180 (0.9)
p
0.09a
0.17b
OR
0.77
1.53
95% CI:
0.57 - 1.04
0.83 - 2.8
Table 4.
Distribution of genotypes, alleles and carriage of minor alleles of BDNF, CPLX2, NTNG1, NGF, NGFR, CHN1, FOS, JUNand IER5 polymorphisms in patients with PTSD and controls.
apcorrected values for comparison of mutant allele frequency between PTSD patients and controls.
bpcorrected values for comparison of mutant allele carriage between PTSD patients and controls.
According to the data obtained, the rs6265*A allele of theBDNF gene was more frequent in controls than in patients (0.19 vs. 0.13, pnominal = 0.03, OR = 0.65, 95% CI: 0.44–0.95). Also, the carriers of rs6265*A minor allele were overrepresented in the group of controls compared to patients (0.36 vs. 0.25, pnominal = 0.02, OR = 1.65, 95% CI: 1.07–2.54). In contrast, the rs1366116*T minor allele of the CPLX2 gene was more frequent among patients compared to controls (0.4 vs. 0.24, pnominal = 0.002, OR = 2.2, 95% CI: 1.4–3.6). Also, the carriers of this allele were more in the group of patients compared to controls (0.61 vs. 0.4, pnominal = 0.008, OR = 0.43, 95% CI: 0.2–0.8). Further, we found that the rs6330*T allele of the NGF gene was overrepresented in patients with PTSD compared to healthy subjects (0.4 vs. 0.2, pnominal = 1.02E-9, OR = 2.64, 95% CI: 1.93–3.61). Also, the carriers of the rs6330*T minor allele (CT + TT) were more frequent in patients than in controls (0.67 vs. 0.35, pnominal = 2.1E-10, OR = 3.77, 95% CI: 2.49–5.70). On the contrary, the frequency (0.33 vs. 0.2, pnominal = 2.0E-6, OR = 0.46, 95% CI: 0.33–0.63) and carriers (0.58 vs. 0.35, pnominal = 6.0E-6, OR = 0.40, 95% CI: 0.27–0.60) of the rs4839435*A minor allele of the NGF gene were higher in controls than in PTSD patients. The NGFR rs734194*T minor allele frequency again was higher in controls than in patients (0.27 vs. 0.1, pnominal = 1.37E-10, OR = 0.28, 95% CI: 0.19–0.42). The same applies to the carriers of the NGFR rs734194*T allele (0.46 vs. 0.18, pnominal = 4.41E-9, OR = 0.26, 95% CI: 0.17–0.42). Also, rs7101*T allele of the FOS gene was more frequent in patients than in controls (0.76 vs. 0.31, pnominal = 2.02E-37, OR = 6.90, 95% CI: 5.05–9.43). The carriers of rs7101*T minor allele were overrepresented in the group of patients compared to controls (0.94 vs. 0.53, pnominal = 6.57E-22, OR = 13.89, 95% CI: 7.28–26.51). In contrast, the rs1063169*T minor allele of the FOS gene was more frequent among controls compared to patients (0.34 vs. 0.1, pnominal = 7.48E-16, OR = 0.23, 95% CI: 0.16–0.33). Also, the carriers of this allele were more in the group of controls compared to patients (0.54 vs. 0.2, pnominal = 8.51E-13, OR = 0.21, 95% CI: 0.13–0.32). After Bonferroni correction, difference in allele frequency between the patient and the control groups for these minor alleles remained significant.
As found in several mental disorders, the risk for PTSD following traumatic event has limited genetic heritability. The genetic understanding of PTSD through candidate gene studies is premature at this point, although several genes hold promise as potential biomarkers. Identifying and understanding the genetics of PTSD will enrich our ability of diagnosis of PTSD. In Figure 1, we summarized the candidate genes responsible for generation and development of PTSD.
Figure 1.
Candidate genes responsible for development of PTSD.
Several studies indicated the association between PTSD and polymorphisms of number of genes of dopaminergic, serotonergic, and GABAergic systems, HPA axis, and other genes related to neurotransmission, neuromodulation, etc. We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, also adding our own results on variations in genes encoding neuro-, immune and apoptotic mediators and regulators, and related transcription factors. Profound understanding of risks in PTSD is possible through classic and convergent genomic approaches and this will lead to development of targeted treatment and prevention approaches. Overall, such researches highlight the potential usefulness of the assessment of target genes’ alteration in diagnosis of PTSD.
References
1.ICD-10. International Statistical Classification of Diseases and Related Health Problems (Edition: 10). Geneva: World Health Organization; 1992.
2.Diagnostic and Statistical Manual of Mental Disorders by American Psychiatric Association (edition 5). Washington, DC; 2013.
3.Dietrich AM. As the pendulum swings: the еtiology of PTSD, complex PTSD, and revictimization. Traumatology 2000;6:41–59.
4.Yehuda R, Giller EL, Levengood RA, Southwick SM, Siever LJ. Hypotalamic-pituitary-adrenal functioning in post-traumatic stress disorder: expanding the concept of the stress response spectrum. Neurobiologial and clinical consequences of stress: from normal adaptation to post-traumatic stress disorder. Hagerstown. MD: Lippincott-Raven; 1991. p. 351–66.
5.Yehuda R. Biology of posttraumatic stress disorder. J Clin Psychiatry 2001;62(17):41–6.
7.Kinchin D. Post traumatic stress disorder: the invisible injury. UK: Success Unlimited; 2005.
8.Amir M, Kaplan Z, Efroni R, Kotler M. Suicide risk and coping styles in post-traumatic stress disorder patients. Psychother Psychosom 1999;68(2):76–81.
9.Young RM, Lawford BR, Noble EP, Kann B, Wilkie A, Ritchie T, Arnold L, Shadforth S. Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol 2002;37(5):451–6.
10.Ben-Ya’acov Y, Amir M. Posttraumatic symptoms and suicide risk. Person Indiv Diff 2004;36:1257–64.
11.Helzer JE, Robins LN, McEvoy L. Post-traumatic stress disorder in the general population. Findings of the epidemiologic catchment area survey. N Engl J Med 1987;317(26):1630–34.
12.Breslau N. The epidemiology of posttraumatic stress disorder: what is the extent of the problem? J Clin Psychiatry 2001;62(17):16–22.
13.Breslau N. Epidemiologic studies of trauma, posttraumatic stress disorder, and other psychiatric disorders. Can J Psychiatry 2002;47(10):923–29.
14.Eley TC, Sugden K, Corsico A, Gregory AM, Sham P. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 2004;9(10):908–15.
15.Afifi TO, Asmundson GJ, Taylor S, Jang KL. The role of genes and environment on trauma exposure and post-traumatic stress disorder symptoms: a review of twin studies. Clin Psychol Rev 2010;30:101–12.
16.Cornelis MC, Nugent NR, Amstadter AB, Koenen KC. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr Psychiatry Rep 2010;12:313–26.
17.Mehta D, Binder EB. Gene × environment vulnerability factors for PTSD: the HPA-axis. Neuropharmacology 2012;62:654–62.
19.Grabe HJ, Lange M, Wolff B, Völzke H, Lucht M. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry 2005;10(2):220–4.
20.Koenen KC. Genetics of posttraumatic stress disorder: review and recommendations for future studies. J Trauma Stress 2007;20:737–50.
21.Broekman BF, Olff M, Boer F. The genetic background to PTSD. Neurosci Biobehav Rev 2007;31:348–62.
22.Amstadter AB, Nugent NR, Koenen KC. Genetics of PTSD: fear conditioning as a model for future research. Psych Ann 2009;39:358–67.
23.Koenen KC, Aiello AE, Bakshis E, Amstadter AB, Ruggiero KJ, Acierno R, Kilpatrick DG, Gelernter J, Galea S. Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. Am J Epidemiol 2009;169:704–11.
24.Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B. PTSD and gene variants: new pathways and new thinking. Neuropharmacology 2012;62:628–37.
25.Digangi J, Guffanti G, McLaughlin KA, Koenen KC. Considering trauma exposure in the context of genetics studies of post-traumatic stress disorder: a systematic review. Biol Mood Anxiety Disord 2013;3:2.
26.Almli LM, Fani N, Smith AK, Ressler KJ. Genetic approaches to understanding post-traumatic stress disorder. Int J Neuropsychopharmacol. 2014; 7(2):355–70.
27.Young RM, Lawford BR, Noble EP, Kann B, Wilkie A, Ritchie T, Arnold L, Shadforth S. Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol 2002;37(5):451–6.
28.Comings DE, Muhleman D, Gysin R. Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol Psychiatry 1996;40:368–72.
29.Voisey J, Swagell CD, Hughes IP, Morris CP, Van Daal A, Noble EP, Kann B, Heslop KA, Young RM, Lawford BR. The DRD2 gene 957C > T polymorphism is associated with posttraumatic stress disorder in war veterans. Depress Anxiety 2009;6(1):28–33.
30.Hemmings SM, Martin LI, Klopper M, van der Merwe L, Aitken L, de Wit E, Black GF, Hoal EG, Walzl G, Seedat S. BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:273–80.
31.Wolf EJ, Mitchell KS, Logue MW, Baldwin CT, Reardon AF, Aiello A, Galea S, Koenen KC, Uddin M, Wildman D, Miller MW. The dopamine D3 receptor gene and posttraumatic stress disorder. J Trauma Stress 2014;27(4):379–87.
32.Dragan WL, Oniszczenko W. The association between dopamine D4 receptor exon III polymorphism and intensity of PTSD symptoms among flood survivors. Anxiety Stress Coping 2009;22:483–95.
33.Segman RH, Cooper-Kazaz R, Macciardi F, Goltser T, Halfon Y, Dobroborski T, Shalev AY. Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 2002;7:903–7.
34.Drury SS, Theall KP, Keats BJ, Scheeringa M. The role of the dopamine transporter (DAT) in the development of PTSD in preschool children. J Trauma Stress 2009;22:534–9.
35.Valente NL, Vallada H, Cordeiro Q, Miguita K, Bressan RA, Andreoli SB, Mari JJ, Mello MF. Candidate-gene approach in post-traumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. J Mol Neurosci 2011;44:59–67.
36.Chang SC, Koenen KC, Galea S, Aiello AE, Soliven R, Wildman DE, Uddin M. Molecular variation at the SLC6A3 locus predicts lifetime risk of PTSD in the Detroit Neighborhood Health Study. PLoS ONE 2012;7:e39184.
37.Mustapic M, Pivac N, Kozaric-Kovacic D, Dezeljin M, Cubells JF, Mück-Seler D. Dopamine beta-hydroxylase (DBH) activity and -1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder. Am J Med Genet Neuropsychiatr Genet 2007;144B(8):1087–9.
39.Kolassa IT, Kolassa S, Ertl V, Papassotiropoulos A, De Quervain DJ. The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferaseVal(158)Met polymorphism. Biol Psychiatry 2010;67:304–8.
40.Valente NL, Vallada H, Cordeiro Q, Bressan RA, Andreoli SB, Mari JJ, Mello MF. Catechol-O-methyltransferase (COMT) val158met polymorphism as a risk factor for PTSD after urban violence. J MolNeurosci 2011;43:516–23.
41.Goenjian AK, Noble EP, Steinberg AM, Walling DP, Stepanyan ST, Dandekar S, Bailey JN. Association of COMT and TPH-2 genes with DSM-5 based PTSD symptoms. J Affect Disord 2014;22(172C):472–8.
42.Kilpatrick DG, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Resnick HS, Roitzsch J, Boyle J, Gelernter J. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane exposed adults. Am J Psychiatry 2007;164:1693–9.
43.Thakur GA, Joober R, Brunet A. Development and persistence of posttraumatic stress disorder and the 5-HTTLPR polymorphism. J Trauma Stress 2009;22:240–3.
44.Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Brady K, Weiss RD, Farrer L, Gelernter J. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry 2009;66:1201–9.
45.Grabe HJ1, Spitzer C, Schwahn C, Marcinek A, Frahnow A, Barnow S, Lucht M, Freyberger HJ, John U, Wallaschofski H, Völzke H, Rosskopf D., Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. Am J Psychiatry 2009;166:926–33.
46.Lee H, Kwak S, Paik J, Kang R, Lee M. Association between serotonin 2A receptor gene polymorphism and posttraumatic stress disorder. Psychiatry Investig 2007;4:104–8.
47.Mellman TA, Alim T, Brown DD, Gorodetsky E, Buzas B, Lawson WB, Goldman D, Charney DS. Serotonin polymorphisms and post-traumatic stress disorder in a Trauma exposed African American population. Depress Anxiety 2009;26:993–7.
48.Goenjian AK, Bailey JN, Walling DP, Steinberg AM, Schmidt D, Dandekar U, Noble EP. Association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms. J Affect Disord 2012;140(3):244–452.
49.Nelson EC, Agrawal A, Pergadia ML, Lynskey MT, Todorov AA, Wang JC, Todd RD, Martin NG, Heath AC, Goate AM, Montgomery GW, Madden PA. Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Mol Psychiatry 2009;14:234–5.
50.Lu AT, Ogdie MN, Jarvelin MR, Moilanen IK, Loo SK, McCracken JT, McGough JJ, Yang MH, Peltonen L, Nelson SF, Cantor RM, Smalley SL. Association of the cannabinoid receptor gene (CNR1) with ADHD and posttraumatic stress disorder. Am J Med Gene Neuropsychiatr Genet 2008;147B:1488–94.
51.Hauer D, Weis F, Papassotiropoulos A, Schmoeckel M, Beiras-Fernandez A, Lieke J, Kaufmann I, Kirchhoff F, Vogeser M, Roozendaal B, Briegel J, de Quervain D, Schelling G. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit Care Med 2011;39(4):643–50.
52.Lian Y, Xiao J, Wang Q, Ning L, Guan S, Ge H, Li F, Liu J. The relationship between glucocorticoid receptor polymorphisms, stressful life events, social support, and post-traumatic stress disorder. BMC Psychiatry 2014;12(14):232.
53.Amstadter AB, Nugent NR, Yang BZ, Miller A, Siburian R, Moorjani P, Haddad S, Basu A, Fagerness J, Saxe G, Smoller JW, Koenen KC. Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients. Dis Markers 2011;30(2–3):89–99. DOI:10.3233/DMA-2011-0761.
54.Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 2011;470(7335):492–7.
55.Uddin M, Chang SC, Zhang C, Ressler K, Mercer KB, Galea S, Keyes KM, McLaughlin KA, Wildman DE, Aiello AE, Koenen KC. Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment. Depress Anxiety 2013;30(3):251–8.
56.Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, Gelernter J. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology 2010;35(8):1684–92.
57.Rothbaum BO, Kearns MC, Reiser E, Davis JS, Kerley KA, Rothbaum AO, Mercer KB, Price M, Houry D, Ressler KJ. Early intervention following trauma may mitigate genetic risk for PTSD in civilians: a pilot prospective emergency department study. J Clin Psychiatry 2014;75(12):1380–7.
58.Sabbagh JJ, O'Leary JC 3rd, Blair LJ, Klengel T, Nordhues BA, Fontaine SN, Binder EB, Dickey CA. Age-associated epigenetic upregulation of the FKBP5 gene selectively impairs stress resiliency. PLoS One 2014;9(9):e107241.
59.Wilker S, Pfeiffer A, Kolassa S, Elbert T, Lingenfelder B, Ovuga E, Papassotiropoulos A, de Quervain D, Kolassa IT. The role of FKBP5 genotype in moderating long-term effectiveness of exposure-based psychotherapy for posttraumatic stress disorder. Transl Psychiatry 2014;4:e403.
60.Szabó C, Kelemen O, Kéri S. Changes in FKBP5 expression and memory functions during cognitive-behavioral therapy in posttraumatic stress disorder: a preliminary study. Neurosci Lett 2014;569:116–20.
61.Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, Price LH, Southwick S, Yang BZ, Rasmussen A, Gelernter J. Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet 2006;141:387–93.
62.Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008; 299(11):1291–305.
63.Pivac N, Kozaric-Kovacic D, Grubisic-Ilic M, Nedic G, Rakos I, Nikolac M, Blazev M, Muck-Seler D. The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder. World J Biol Psychiatry 2012;13(4):306–11.
64.Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA. The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biol Psychiatry 2013;73(11):1059–63.
65.Miller JK, Wiener JM. PTSD recovery, spatial processing, and the val66met polymorphism. Front Hum Neurosci 2014;8:100.
66.Zhang L, Benedek DM, Fullerton CS, Forsten RD, Naifeh JA, Li XX, Hu XZ, Li H, Jia M, Xing GQ, Benevides KN, Ursano RJ. PTSD risk is associated with BDNF Val66Met and BDNF overexpression. Mol Psychiatry 2014;19(1):8–10.
67.Freeman T, Roca V, Guggenheim F, Kimbrell T, Griffin WS. Neuropsychiatric associations of apolipoprotein E alleles in subjects with combat-related posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci 2005;17(4):541–3.
68.Lyons MJ, Genderson M, Grant MD, Logue M, Zink T, McKenzie R, Franz CE, Panizzon M, Lohr JB, Jerskey B, Kremen WS. Gene-environment interaction of ApoE genotype and combat exposure on PTSD. Am J Med Genet B Neuropsychiatr Genet 2013;162B(7):762–9.
69.Kim TY, Chung HG, Shin HS, Kim SJ, Choi JH, Chung MY, An SK, Choi TK, So HS, Cho HS. Apolipoprotein E gene polymorphism, alcohol use, and their interactions in combat-related posttraumatic stress disorder. Depress Anxiety 2013;30(12):1194–201.
70.Pivac N, Knezevic J, Kozaric-Kovacic D, Dezeljin M, Mustapic M, Rak D, Matijevic T, Pavelic J, Muck-Seler D. Monoamine oxidase (MAO) intron 13 polymorphism and platelet MAO-B activity in combat-related posttraumatic stress disorder. J Affect Disord 2007;103(1–3):131–8.
71.Sah R, Geracioti TD. Neuropeptide Y and posttraumatic stress disorder. Mol Psychiatry 2013;18(6):646–55.
72.Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck C, Rosenheck RA, Cramer J, Southwick S, Charney D, Krystal J, Gelernter J. A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 2002;59:825–31.
73.Nievergelt CM, Maihofer AX, Mustapic M, Yurgil KA, Schork NJ, Miller MW, Logue MW, Geyer MA, Risbrough VB, O'Connor DT, Baker DG. 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. Psychoneuroendocrinology 2015;51:459–71.
74.Amstadter AB, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, Gelernter J. Variant in RGS2 moderates post-traumatic stress symptoms following potentially traumatic event exposure. J Anxiety Disord 2009;23:369–73.
75.Sakamoto M, Fujisawa Y, Nishioka K. Physiologic role of the complement system in host defense, disease, and malnutrition. Nutrition 1998;14(4):391–8.
76.Volankis JE, Frank MM: The human complement system in health and disease. New York: Mircel Dekker Inc; 1998.
77.Mollnes TE, Song W-C, Lambris JD. Complement in inflammatory tissue damage and disease. Trends Immunol Today 2002;23(2):61–6.
78.Morgan BP, Gasque P, Singhrao SK, Piddlesden SJ. The role of complement in disorders of the nervous system. Immunopharmacology 1997;38(1–2):43–50.
79.Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Amer J Pathol 1999;154(3):927–36.
80.Gasque P, Neal JW, Singhrao SK, McGreal EP, Dean YD, Van BJ, Morgan BP. Roles of the complement system in human neurodegenerative disorders: pro-inflammatory and tissue remodeling activities. MolNeurobiol 2002;25(1):1–17.
81.Francis K, Van Beek J, Canova C, Neal JW, Gasque P: Innate immunity and brain inflammation: the key role of complement. Expert Rev Mol Med 2003;5(15):1–19.
82.Van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y AcadSci 2003;992:56–71.
83.Boyajyan A, Zakharyan R, Khoyetsyan A. Chapter XI. Molecular and genetic indicators of aberrant immunity and apoptosis in schizophrenia In: Sumiyoshi T editor. Schizophrenia Research: Recent Advances: Nova Science Publishers; 2012, pp.183–240.
84.Maes M, Hendriks D, Van Gastel A, Demedts P, Wauters A, Neels H, Janca A, Scharpé S. Effects of psychological stress on serum immunoglobulin, complement, and acute phase protein concentrations in normal volunteers. Psychoneuroendocrinology 1997;22:397–409.
85.Burns V, Edwards K, Ring C, Drayson M, Carroll D: Complement cascade activation after an acute psychological stress task. Psychosomatic Medicine 2008;70:387–396.
86.Liu D, Xiao B, Han F, Wang E, Shi Y. Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder. BMC Psychiatry 2012;12:211.
87.Han F, Yan S, Shi Y. Single-prolonged stress induces endoplasmic reticulum-dependent apoptosis in the hippocampus in a rat model of post-traumatic stress disorder. PLoS One 2013;8(7):e69340.
88.Li Y, Han F, Shi Y. Increased neuronal apoptosis in medial prefrontal cortex is accompanied with changes of Bcl-2 and Bax in a rat model of post-traumatic stress disorder. J Mol Neurosci 2013;51(1):127–37.
89.Wang J, Guo C, Liu S, Qi H, Yin Y, Liang R, Sun MZ, Greenaway FT. Annexin A11 in disease. Clin Chim Acta 2014;431:164–8.
90.Hong M, Park N, Chun YJ. Role of annexin a5 on mitochondria-dependent apoptosis induced by tetramethoxystilbene in human breast cancer cells. Biomol Ther 2014;22(6):519–24.
91.Shibata H, Kanadome T, Sugiura H, Yokoyama T, Yamamuro M, Moss SE, Maki M2. Anew role for annexin A11 in the early secretory pathway via stabilizing Sec31A at the endoplasmic reticulum exit sites (ERES). J Biol Chem 2014;pii:jbc.M114.592089. [Epub ahead of print].
92.Mkrtchyan GM, Boyadzhyan AS, Avetyan DG, Sukiasyan SG. Involvement of anomalous apoptosis in impairments to synaptic plasticity in post-traumatic stress disorder. Neurosci Behav Physiol 2014;44(4):442–6.
93.Boyajyan A, Mkrtchyan G, Hovhannisyan L, Avetyan D. Chapter 5 Alterations in the immune response, apoptosis and synaptic plasticity in posttraumatic stress disorder: molecular indicators and relation to clinical symptoms. In: Durbano F ed. New Insights Into Anxiety Disorders: In Tech 2013;p.105–33.
94.Glynn D, Gibson HE, Harte MK, Reim K, Jones S, Reynolds GP, Morton AJ. Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse. Hum Mol Genet 2010;19(17):3402–12.
95.McMahon HT, Missler M, Li C, Sudhof TC. Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 1995;83:111–9.
96.Reim K, Wegmeyer H, Brandstatter JH, Xue M, Rosenmund C, Dresbach T, Hofmann K, Brose N. Structurally and functionally unique complexins at retinal ribbon synapses. J. Cell Biol 2005;169:669–80.
97.Eastwood SL, Harrison PJ. Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 2000;5:425–32.
98.Eastwood SL, Harrison PJ. Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull 2001;55:569–78.
99.Knable MB, Barci BM, Webster, MJ, Meador-Woodruff J, Torrey EF. Stanley Neuropathology Consortium Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol Psychiatry 2004;9:609–20.
100.Sawada K, Young CE, Barr AM, Longworth K, Takahash S, Arango V, Mann JJ, Dwork AJ, Falkai P, Phillips AG, Honer WG. Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol Psychiatry 2002;7:484–92.
101.Morton AJ, Faull RL, Edwardson JM. Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 2001;56:111–7.
102.DiProspero NA, Chen EY, Charles V, Plomann M, Kordower JH, Tagle DA. Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol 2004;33:517–33.
103.Harrison PJ, Eastwood SL. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 1998;352:1669–73.
104.Eastwood SL, Burnet PW, Harrison PJ. Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain. Synapse 2000;36:167–77.
105.Eastwood SL, Cotter D, Harrison PJ. Cerebellar synaptic protein expression in schizophrenia. Neuroscience 2001;105:219–29.
106.Eastwood SL, Harrison PJ. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr Res 2005;73:159–72.
107.Sawada K, Barr AM, Nakamura M, Arima K, Young CE, Dwork AJ, Falkai P, Phillips AG, Honer WG. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 2005;62:263–72.
108.Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 2004;4:3943–52.
109.Tannenberg RK, Scott HL, Tannenberg AE, Dodd PR. Selective loss of synaptic proteins in Alzheimer’s disease: evidence for an increased severity with APOE varepsilon4. Neurochem Int 2006;49:631–9.
110.Qiao LY. Neurotrophin signaling and visceral hypersensitivity. Front Biol 2014;9(3):216–24.
Written By
Boyajyan Anna, Avetyan Diana, Hovhannisyan Lilit and Mkrtchyan
Gohar
Submitted: 29 October 2014Reviewed: 23 February 2015Published: 09 September 2015
Open access peer-reviewed chapter
