ISSN 10227954, Russian Journal of Genetics, 2013, Vol. 49, No. 6, pp. 667–672. © Pleiades Publishing, Inc., 2013. Original Russian Text © Z.L. Khalilova, A.G. Zainullina, A. R. Valiullina, G.G. Zakharova, R.G. Valinurov, E.K. Khusnutdinova, 2013, published in Genetika, 2013, Vol. 49, No. 6, pp. 767–772.
HUMAN GENETICS
Association of YWHAE Gene Polymorphism with Suicidal Behavior Z. L. Khalilovaa, A. G. Zainullinaa, A. R. Valiullinab, G. G. Zakharovac, R. G. Valinurovc, and E. K. Khusnutdinovaa, b a
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, 450054 Russia email:
[email protected] b Department of Genetics and Fundamental Medicine ofBashkir State University, Ufa, 450054 Russia c Bashkir Republic Psychiatric Hospital No. 1, Ufa, 450069 Russia Received June 21, 2012; in final form August 17, 2012
Abstract—The importance of YWHAE gene polymorphisms (rs1532976, rs3752826, and rs9393) in the development of suicidal behavior has been studied in ethnic groups of Russians and Tatars from the Republic of Bashkortostan. It was revealed that the carriers of the YWHAE*C allele of rs3752826 polymorphism of the YWHAE gene have increased the risk of suicidal behavior (OR = 1.91), regardless of their ethnicity. In addi tion, the YWHAE*T allele of rs9393 polymorphism (OR = 2.21), YWHAE*T/*T genotype (OR = 2.73), and YWHAE*T allele (OR = 1.52) of the rs1532976 polymorphism, as well as the YWHAE*A*T haplotype of rs1532976 and rs9393 polymorphisms (OR = 1.54) represent genetic markers of the risk of suicidal behavior in the sample of subjects of Russian ethnicity. DOI: 10.1134/S1022795413030095
INTRODUCTION Members of the YWHA protein family represent highly effective regulators of apoptosis, cell cycle, divi sion, transcription, replication, ion channel, and transmitter functioning, as well as cytoskeleton orga nization [1–3]. YWHA (1433) family proteins were discovered in the nerve tissue, where their quantities exceed 1% of the proteome [4, 5]. YWHA proteins contain at least two regions that are responsible for the binding of phosphorylated ligands with distinct pri mary structure. This permits YWHA proteins to bind target proteins, thus increasing the enzyme activity and controlling their intracellular localization [6]. Many studies have recently reported on the involvement of YWHA proteins in the development of some neurodegenerative disorders [7, 8] and psychic diseases [9, 10]. It was demonstrated that the concen tration of YWHA protein in cerebrospinal liquid is increased in various types of dementias, encephalopa thies, and tumors of the central nervous system. It was established that YWHA proteins activate the key enzymes of serotonin and catecholamine synthesis, i.e., tryptophan and tyrosine monooxygenases [11]. In human tissues, seven isoforms of YWHA protein were found, including β, γ, ε, η, σ, τ/θ, and ζ [12]. Each isoform is encoded by a specific gene [13]. Evi dence has been presented on the association of genes of the YWHA family with various forms of cancer [14], Alzheimer’s disease [8, 15, 16], Down syndrome [15], Miller–Dieker lissencephaly syndrome [17, 18], Ger stmann–Straussler–Scheinker syndrome [7], Creutzfeldt–Jacob disease [19, 20], bipolar disorder
[21, 22], depression [23], schizophrenia [21, 24–26], and suicide [10]. With regard to psychiatric disorders, two genes are the best known, i.e., YWHAH, which encodes etapolypeptide 1433η, which is located on the 22q12.3 chromosome [22], and the YWHAE gene, which encodes epsilon peptide, 1433ε, which is located on the 17p13.3 human chromosome [9]. The YWHAH gene is expressed in the brain and is involved in the regulation of the hypothalamus–hypo physis–adrenaline system and is considered to be a functional candidate gene in schizophrenia [27] and bipolar disorder [22, 28] studies. The studies of Sekiguchi et al. [29] have shown that alterations in the expression of the YWHAE gene cause the dysfunction of several neurotransmitters, such as serotonin, dopamine, and noradrenalin. The distur bances in the axon fibrillar structure of the prefrontal cerebral cortex were observed in YWHAE gene knock out mice. Another study of YWHAE gene knockout mice has shown that a 50% decrease in gene expres sion resulted in cognitive disorders, specifically weak defects in working memory [9]. The association of the YWHAE gene with psychiatric diseases in the popula tions of Western Europe, North America, and Japan has also been reported [9, 10, 15, 24]. A previous genomewide study has shown the association of three polymorphic loci, rs1532976, rs3752826, and rs9393, of the YWHAE gene with successful suicides in the Japanese population [10]. The molecular genetic studies related to the analysis of associations of the polymorphism of the YWHAE gene with suicidal behavior (SB) have not been conducted previously in
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Bashkortostan. Considering the ethnic diversity of the Republic of Bashkortostan, this study is timely. There fore, the aim of our study was to explore the role of three polymorphisms (rs1532976, rs3752826, and rs9393) of the YWHAE gene in the development of sui cidal behavior in ethnic groups of Russians and Tatars from Bashkortostan. MATERIALS AND METHODS The study included 236 subjects (127 of Russian ethnicity and 109 of Tatar ethnicity), who had attempted suicide (average age 31.84 ± 14.79 years) and were kept in intensive care at the time when blood was drawn at Ufa City Clinical Hospital no. 21. The gender composition of the sample was as follows: 64% female and 36% male. Among the methods of attempted suicide, poisoning was observed in 81.3% cases, exsanguination was observed in 8.3%, blunt force trauma in 6.2%, and asphyxiation in 4.2%. The control group consisted of 362 healthy donors of comparable age (average age 30.0 ± 10.0), gender (38% male and 62% female), and ethnicity (134 Rus sians and 228 Tatars) to the samples from patients who were not under psychiatrist observation and declining the hereditary load of psychic diseases. All of the examined subjects signed the Informed Consent Form regarding their involvement in the study after obtaining knowledge about the experiment details. This study was approved by the local ethics committee of the Institute of Biochemistry and Genetics, Ufa Scientific center Russian Academy of Sciences. DNA was isolated using the phenolchloroform extraction method from whole peripheral venous blood [30]. The amplification of the examined loci was conducted by the polymerase chain reaction of DNA synthesis. To identify nucleotide substitutions, the amplified fragments were hydrolyzed by an appropri ate restriction endonuclease [10]. The separation of DNA fragments was conducted by gel electrophoresis in 7% polyacrylamide gel. Afterwards, the gel was stained by ethidium bromide and visualized in the passing ultraviolet light. Statistical analysis was conducted using the follow ing software: Statistica for Windows XP; Microsoft Excel 2003; and Quantitative Skills, including its interactive BIOSTAT version. A comparison of the genotype frequency distribution, as well as an analysis of the binary data, we calculated the χ2 test and P probability (values of P < 0.05 were considered to be statistically significant). In the comparison of the binary data, odd ratio (OR) indices and 95% confi dential intervals (CI) were also calculated [31]. The construction of haplotype blocks, analysis of haplotypes, and evaluation of linkage disequilibrium between two or more polymorphic markers were con ducted using Haploview v. 4.1 Software [32]. Rare
genotypes (with the frequency of less than 2%) were excluded from the association analysis. RESULTS AND DISCUSSION The results of the present study are presented in Table 1. In all examined samples, the frequency of the genotype distribution of the YWHAE gene corre sponded to the Hardy–Weinberg distribution. A comparative analysis of the SB patients and healthy subjects in the total group has shown signifi cant differences in the distribution of allele (χ2 = 5.28; d.f. = 1, P = 0.02) and genotype (χ2 = 5.57; d.f. = 1, P = 0.018) frequencies in the rs3752826 polymorphism of the YWHAE gene. The YWHAE*C allele frequency was significantly higher in the SB patient sample (OR = 1.91, 95% CI 1.0–3.36). A comparative analysis of the allele and genotype frequencies of the rs9393 polymorphism of the YWHAE gene in the total group of SB patients and healthy controls has also shown significant differences (χ2 = 10.037; d.f. = 1, P = 0.0024 and χ2 = 8.99; d.f. = 2, P = 0.01, respectively). These differences resulted from the high YWHAE*T allele frequency (OR = 2.16, 95% CI 1.32–3.57) and YWHAE*T/*T genotype fre quency (χ2 = 8.13; d.f. = 2; Р = 0.005; OR = 2.12, 95% CI 1.25–3.63) in SB patients. Upon a comparative analysis of the allele frequency distribution of the rs9393 polymorphism of the YWHAE gene between groups of SB patients and healthy subjects of Russian ethnicity, a significant difference (χ2 = 3.93; d.f. = 1, P = 0.04) was revealed due to the high frequency of the YWHAE*T allele (OR = 2.21, 95% CI 1.01–4.93) in SB patients. An analysis of the genotype frequency distribution of the rs1532976 polymorphism of the YWHAE gene in the Russian ethnic sample showed a significant differ ence (χ2 = 6.53; d.f. = 2, P = 0.038) due to the high frequency of the YWHAE*T/*T genotype in SB patients versus the control sample (χ2 = 5.59; d.f. = 2; P = 0.018; OR = 2.73, 95% CI 1.17–6.50). An analysis of the allele distribution frequency in he Russian eth nic sample has shown a significant increase in the YWHAE*T allele of the rs1532976 polymorphism of the YWHAE gene (χ2 = 5.058; d.f. = 1; P = 0.0245; OR = 1.52, 95% CI 1.037–2.22) in the SB patient sample. A comparative analysis of the allele and genotype distribution in the three examined loci of the YWHAE gene did not show significant differences between SB patients and control subjects of the Tatar ethnic group. In the examined samples, we subsequently con ducted an analysis of the haplotype associations of the YWHAE gene and three polymorphisms (rs1532976, rs3752826, and rs9393) in SB patients (Table 2). The linkage disequilibrium analysis in the Tatar ethnic group has shown the linkage between all examined loci of the YWHAE gene in the pairwise approach (D' val ues varied from 0.39 to 0.88). This enabled us to con
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Table 1. Genotype and allele frequency distribution in YWHAE gene polymorphisms in SB subjects and healthy donors Genotype, allele
Total patients
Russians control
patients
Tatars control
patients
control
rs1532976 N
226
359
122
134
104
225
*T/*T
38 (0.17)
41 (0.11)
22 (0.18)
10 (0.075)
16 (0.15)
31 (0.14)
*T/*C
103 (0.46)
160 (0.45)
51 (0.42)
64 (0.47)
52 (0.50)
96 (0.43)
*C/*C
85 (0.38)
158 (0.44)
49 (0.40)
60 (0.45)
36 (0.35)
98 (0.43)
*T
179 (0.32)
242 (0.34)
95 (0.39)
84 (0.31)
84 (0.40)
158 (0.35)
*C
378 (0.68)
476 (0.66)
149 (0.61)
184 (0.69)
124 (0.60)
292 (0.65)
rs3752826 N
211
364
115
135
96
229
*A/*A
181 (0.86)
336 (0.92)
99 (0.86)
125 (0.93)
82 (0.85)
211 (0.92)
*C/*A
30 (0.14)
28 (0.08)
16 (0.14)
10 (0.07)
14 (0.15)
18 (0.08)
*C
392 (0.93)
700 (0.96)
214 (0.93)
260 (0.96)
178 (0.93)
440 (0.96)
*A
30 (0.07)
28 (0.04)
16 (0.07)
10 (0.04)
14 (0.07)
18 (0.04)
*C/*C
rs9393 N
234
330
125
102
109
228
*T/*T
211 (0.90)
262 (0.80)
115 (0.92)
82 (0.80)
96 (0.88)
180 (0.79)
*T/*C
21 (0.09)
64 (0.18)
9 (0.07)
18 (0.18)
12 (0.11)
46 (0.20)
*C/*C
2 (0.01)
4 (0.01)
1 (0.008)
2 (0.02)
1 (0.01)
2 (0.01)
*T
443 (0.95)
588 (0.89)
239 (0.96)
182 (0.91)
204 (0.93)
406 (0.89)
*C
25 (0.05)
72 (0.11)
11 (0.04)
22 (0.09)
14 (0.06)
50 (0.11)
Note: N is number of subjects.
struct one haplotype block of 60 kb. No significant dif ferences were found in the analysis of the haplotype distribution frequency (χ2 = 7.08; d.f. = 4; Р = 0.132) between the examined samples of SB patients and control subjects of Tatar ethnic group. The linkage disequilibrium analysis has shown a linkage between the rs1532976, and rs9393 gene poly morphisms (D' = 0.68), as well as between the rs1532976 and rs3752826 gene polymorphisms (D' = 0.86) of the YWHAE gene in the Russian ethnic group. Therefore, we have constructed two 60kb (block 1) and 43kb (block 2) haplotype blocks. In the analysis of the haplotype frequency distribution in block 1, a significant difference has been revealed between the SB patients and control subjects (χ2 = 10.98; d.f. = 2; Р = 0.004) due to the high frequency of the YWHAE*А*Т haplotype (χ2 = 5.08; d.f. = 1, Р = RUSSIAN JOURNAL OF GENETICS
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0.025; OR = 1.54, 95% CI 1.06–2.24) in the SB patients. An analysis of the haplotype frequency distribution in block 2 between SB patients and control subjects has shown a significant difference (χ2 = 6.75; d.f. = 2 P = 0.034) due to the prevalence of the carriers of the YWHAE*Т*Т haplotype (χ2 = 3.79; d.f. = 1, Р = 0.052) in SB patients (Table 2). Thus, our results sup port the previous observations of others on the associ ation of the YWHAE gene with SB. In the study by Yanagi et al. [10], the association of haplotypes of the rs1532976, rs3752826, and rs9393 polymorphisms of the YWHAE gene with successful suicides (Р = 0.0005) has been revealed in the Japa nese population. The increased expression of the YWHAE gene in the postmortem brains of suicide victims has also been shown. 2013
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Table 2. Haplotype distribution frequency of YWHAE gene (rs1532976, rs3752826, and rs9393) analysis in the exam ined groups Haplotypes
N
Patients
Control
Russians Block 1
Block 2
*A*C
155
0.522
0.654
*A*T
93
0.407
0.309
*C*C
13
0.071
0.032
*T*C
152
0.552
0.608
*T*T
92
0.396
0.310
*C*C
16
0.041
0.078
Tatars *T*A*C
172
0.487
0.520
*T*A*T
117
0.380
0.331
*C*A*C
25
0.045
0.089
*T*C*C
16
0.064
0.039
*C*A*T
7
0.019
0.021
Note: N is number of subjects.
The DISC1 gene, which is associated with the development of the majority of psychiatric diseases, including schizophrenia, depressive disorders, and bipolar disturbances, is involved in the development of the nervous system, including the maturation of the cerebral cortex [33]. DISC1 protein forms a complex based on the interaction with other proteins, including YWHAE. Therefore, two genomewide association studies of psychiatric disorders were performed [9, 34]. In the study by Ikeda et al. [9], the association of rs3752826, rs1532976, and rs9393 polymorphisms of the YWHAE gene with schizophrenia in the Japanese population has been shown. At the same time, Liu et al. [34] failed to identify any such association in the Chinese population. Some studies reported the association of the YWHAE gene with neurogenesis. At the same time, neurogenesis disturbance underlies the etiology of sui cidal behavior. It has been shown that the low level of serotonin and dopamine neurotransmitters is accom panied by a decrease in neurogenesis in the hippocam pus where cells capable of dividing are concentrated [10]. With prolonged use of antidepressants, an inhib itor of reversed serotonin capture, admission neuro genesis was stimulated in rats [23], while the depletion of serotonin in the brain by a decrease in neurotoxins resulted in neurogenesis [35, 36]. It has been estab lished that lithium and clozapine drugs, which are
considered efficient at preventing suicide [37–40], stimulate neurogenesis in the dentate gyrus in rodents [41]. It has been found recently that YWHAE is involved in neuronal migration, which is a part of neu rogenesis [18]. Because YWHAE is functionally asso ciated with neurogenesis and TPH activity, the increased content of YWHAE in suicide victims indi cate the compensating response of the decrease in neurogenesis under stress conditions and the attenu ated transmission of serotonin. Two pharmacogenetic studies have shown that mood stabilizers, such as lithium and valproate, which are used to treat bipolar disorders, affect the YWHAE concentration. This indicates its role in mood regula tion [38, 39]. Fluoxetine, a selective inhibitor of sero tonin reuptake, increases the immunoreactivity of YWHAE proteins in the hippocampus and dorsal raphe nucleus, as well as stimulates the tryptophan expression [42]. Our results show that the presence of the *C allele of the rs3752826 polymorphism of the YWHAE gene (OR = 1.91) is a factor that increases the risk of SB in the examined subjects, regardless of ethnicity, while the incidence the *T allele (OR = 2.21) of the rs9393 polymorphism, the *T/*T genotype (OR = 2.73) and *T allele (OR = 1.52) of the rs1532976 polymorphism, and the *A*T haplotype of the rs1532976 and rs9393 polymorphisms of the YWHAE gene (OR = 1.54) are factors that increase the SB risk in the examined sam ple of Russian ethnicity. Thus, SB studies are currently being carried out and, despite significant progress, they are still impor tant in the etiology and pathogenesis of the disease, and the contribution of the genetic component in its development are still not fully understood. The studies of the molecular mechanisms of SB are important for the development of more economic and effective methods for the early diagnosis, prevention, treat ment, and rehabilitation of SB patients. ACKNOWLEDGMENTS The study was partially funded by the Russian Foundation for Humanities (project no. 1106 00554a). REFERENCES 1. Sluchanko, N.N., Gusev, N.B., The 1433 Proteins and the Cytoskeleton Regulation, Usp. Boil. Khim., 2010, vol. 50, pp. 69–116. 2. Colson, N., Dodd, P., and Lewohl, J., Differential Expression of 1433 Isoforms in Human Alcoholic Brain, Alcohol Clin. Exp. Res., 2011, vol. 35, no. 6, pp. 1041–1049. 3. Morrison, D., The 1433 Proteins: Integrators of Diverse Signaling Cues That Impact Cell Fate and Cancer Development, Trends Cell Biol., 2009, vol. 19, pp. 16–23.
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