Psychiatry Research 225 (2015) 744–745
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between Silent Information Regulator 1 (SIRT1) gene polymorphisms and schizophrenia in a Chinese Han population To the Editors: Schizophrenia is a common mental illness with a complex etiology involving a multitude of susceptibility genes. Historically, the predominant explanation for schizophrenia has been the “dopamine hypothesis”, which states that genes involved in the dopaminergic signal transduction system contribute to the pathogenesis of schizophrenia and (or) to the expression of symptoms (Godar and Bortolato, 2014). Silent Information Regulator 1 (SIRT1) has been implicated in a variety of cellular functions, including circadian rhythms and dopaminergic signaling (Park et al., 2011; Shuto et al., 2013). A case-control study of Japanese schizophrenia and bipolar patients revealed an association between schizophrenia and two SIRT1 haplotypes involving four single nucleotide polymorphisms (SNPs) (Kishi et al., 2011). These results suggest that altered expression, mutations, and (or) polymorphisms of SIRT1 may be involved in the pathogenesis of schizophrenia. However, there are no studies testing such an association in the Chinese population. Here, we conducted a case-control study to investigate the association between four SIRT1 SNPs (rs3758391C/T, rs4746720C/T, rs10997875C/T and rs3740051A/G) and schizophrenia in Chinese Han subjects. We studied 376 unrelated schizophrenia patients (238 males and 138 females, mean age: 47.42 years, SD¼10.06, range, 20 72 years), and 569 healthy control subjects (271 males and 298 females, mean age: 32.14 years, SD¼7.77, range: 21 60 years). All were screened by experienced psychiatrists before collecting blood samples for genotyping. Clinical diagnosis was made independently by two senior psychiatrists based on structured interviews and a review of medical records following DSM–IV (American Psychiatric Association) criteria. The polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism analysis according to the methods described in our previous study (Ma et al., 2013). All the protocols were approved by the Ethics Committee of China Medical University. Allele frequencies and genotypes were estimated by the gene-counting method, and differences in distribution between cases and controls were tested using χ2 analysis or Fisher's test. We also performed linkage disequilibrium analysis and haplotype frequency comparison of the four polymorphisms using Haploview version 4.2. Allele, genotype and haplotype frequencies were also assessed separately for males and females. The SIRT1 genotype distribution of the control group was consistent with Hardy–Weinberg equilibrium (χ2 ¼0.253, 0.420, 0.711, 3.211; P¼0.615, 0.517, 0.399, 0.073, respectively). Compared with the healthy control subjects, the frequencies for AA genotypes (χ2 ¼ 22.891, P¼0.000) and A allele (χ2 ¼ 18.328, P¼ 0.000, OR¼ 0.608, 95% CI¼0.484–0.765) of the rs3740051A/G polymorphism were http://dx.doi.org/10.1016/j.psychres.2014.11.027 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
significantly higher in the schizophrenic patients (Table 1). And in gender-specific analyses, there were significant differences in the frequencies of the genotype (male: χ2 ¼ 11.575, P¼ 0.003; female: χ2 ¼11.903, P¼ 0.003) and allele (male: χ2 ¼ 9.810, P¼ 0.002, OR¼0.621, 95%CI¼0.460–0.838; female: χ2 ¼8.979, P¼ 0.003, OR¼0.574, 95%CI¼0.398–0.828) between the patients and controls (Table 1). In the whole study group, a strong pair-wise linkage disequilibrium of the SIRT1 gene was found among the four SNPs, and the same result was found when samples were divided by sex (all |D0 |40.85). The frequencies of the TGTT haplotype were significantly higher in the control subjects, while the CATT haplotype frequencies were significantly higher in the patients for both the whole subjects (χ2 ¼15.982, 11.358, P¼0.000, 0.001) and subjects grouped by gender (male: χ2 ¼9.712, 4.158, P¼0.002, 0.042; female: χ2 ¼10.615, 7.970, P¼ 0.001, 0.005). Additionally, we also observed higher TATT haplotype frequencies in the patients for both the whole subjects (χ2 ¼8.731, P¼ 0.003) and the female subjects (χ2 ¼5.347, P¼ 0.021). Our results suggest that the Chinese subjects carrying the A allele (AA genotype) of the rs3740051A/G polymorphism or the CATT and TATT haplotypes may be more at risk for schizophrenia, while subjects carrying the TGTT haplotype may have a reduced risk accordingly. The aforementioned Japanese study (Kishi et al., 2011) found an association between rs4746720 and schizophrenia, although the correlation was no longer significant after Bonferroni correction. Genetic heterogeneity between Chinese Han and Japanese populations as well as systematic differences in environments may account for the difference in the strength of the rs4746720 association between these populations. On the other hand, the significant association of two haplotypes of 4 SIRT1 SNPs (rs12778366T/C, rs2273773T/C, rs4746720T/C, and rs10997875T/ C; TTTT and TTCT) with schizophrenia in the Japanese cohort together with our result suggests that SIRT1 may be a promising susceptibility gene for schizophrenia. For the same chromosomal region or gene, however, the strength of the correlation can vary markedly among populations, so positive results in one ethnic population must be confirmed in others. Han Chinese account for a significant proportion of the world's total population, and for an approximately equivalent proportion of all schizophrenics. Therefore, the association analysis between the SIRT1 gene and schizophrenia in the Chinese Han population is of theoretical and practical significance. In conclusion, our results suggest an association between the SIRT1 gene and schizophrenia in the Chinese Han population, although the effects of the identified haplotype on regional SIRT1 expression and function remain to be determined. We speculate that this particular variant may disrupt circadian rhythms and (or) DA signaling, thereby contributing to disease pathogenesis and (or) expression. However, further studies are required to replicate in different ethnic groups. Furthermore, schizophrenia is a polygenic disease, so large samples are required to reveal the minor effects of single genes. Nonetheless, this study provides further evidence that allelic variants of SIRT1 contribute to schizophrenia risk, at least in Asian populations.
Letter to the Editor / Psychiatry Research 225 (2015) 744–745
745
Table 1 Genotype and allele distribution of the four analyzed SNPs in schizophrenia patients and controls. SNP
Patient, n(%)
Controls, χ2 n (%)
P
OR (95%CI)
rs3758391 Genotypes CC 21(5.6) 16(2.8) CT 89(23.7) 149(26.2) TT 266(70.7) 404(71.0) 5.018 0.081 Alleles C 131(17.4) 181(15.9) T 621(82.6) 957(84.1) 0.754 0.385 1.115 (0.872– 1.427) rs4746720 Genotypes CC 77(20.5) 105(18.5) CT 178(47.3) 270(47.4) TT 121(32.2) 194(34.1) 0.732 0.694 Alleles C 332(4414) 480(42.2) T 420(55.9) 658(57.8) 0.717 0.397 1.084 (0.900– 1.305) rs10997875 Genotypes CC 5(1.3) 12(2.1) CT 110(29.3) 159(28.0) TT 261(69.4) 398(69.9) 0.910 0.634 Alleles C 120(16.0) 183(16.1) T 632(84.0) 955(83.9) 0.005 0.943 0.991 (0.771– 1.274) rs3740051 Genotypes GG AG AA Alleles G A
a
Male Male Patients, n(%) Controls, n (%)
13(5.5) 58(24.4) 167(70.2)
7(2.6) 70(25.8) 194(71.6)
84(17.6) 392(82.4)
84(15.5) 458(84.5)
46(19.3) 117(49.2) 75(31.5)
45(16.6) 136(50.2) 90(33.2)
209(43.9) 267(56.1)
226(41.7) 316(58.3)
3(1.3) 69(29.0) 166(69.7)
5(1.8) 75(27.7) 191(70.5)
75(15.8) 401(84.2)
85(15.7) 457(84.3)
3(1.3) 82(34.5) 153(64.3)
12(4.4) 121(44.7) 138(50.9)
134(17.8) 299(26.3) 88(18.5) 618(82.2) 839(73.7) 18.328 0.000a 0.608 (0.484– 388(81.5) 0.765)
145(26.8) 397(73.2)
3(0.8) 31(5.4) 128(34.0) 237(41.7) 245(65.2) 301(52.9) 22.891 0.000a
χ2
P
2.817 0.245
OR (95%CI)
Female Female χ2 Patients, n(%) Controls, n (%)
8(5.8) 31(22.5) 99(71.7)
47(17.0) 0.849 0.357 1.168 (0.839– 229(83.0) 1.627)
0.665 0.717
31(22.5) 61(44.2) 46(33.3)
123(44.6) 0.506 0.477 1.094 (0.853– 153(55.4) 1.404)
0.363 0.834
2(1.4) 41(29.7) 95(68.9)
45(16.3) 0.001 0.974 1.006 (0.717– 231(83.7) 1.410)
11.575 0.00a
0(0.0) 46(33.3) 92(66.7)
46(16.7) 9.810 0.002a 0.621 (0.460– 230(83.3) 0.838)
9(3.0) 79(26.5) 210(70.5) 97(16.3) 499(83.7)
60(20.1) 134(45.0) 104(34.9) 254(42.6) 342(57.4)
7(2.3) 84(28.2) 207(69.5) 98(16.4) 498(83.6)
19(6.4) 116(38.9) 163(54.7) 154(25.8) 442(74.2)
P
OR (95%CI)
2.499 0.287
0.078 0.780 1.056 (0.721–1.54)
0.325 0.850
0.292 0.589 1.082(0.812– 1.443)
0.451 0.798
0.003 0.959 0.990 (0.673– 1.456)
11.903 0.003a
8.979 0.003a 0.574 (0.398– 0.828)
P o0.05 is taken to indicate statistical significance.
Conflict of interest
Yuan Wang, Yinglin Huang, Miao Peng Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China Department of Psychology, Shengjing Hospital of China Medical University, Shenyang 110022, China
All authors declare that they have no conflicts of interest. Acknowledgments
Zhengtu Cong, Xin Li, Ailu Lin, Gang Zhu n Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China E-mail address: [email protected] (G. Zhu)
This study was supported by a grant from a project of Liaoning SHIBAIQIAN high-end talent, a grant from Liaoning Science & Technology project (2011408004), and a grant from National Natural Science Foundation of China (81271442) for Prof. Gang Zhu.
Longyan Peng The Third Hospital of Daqing, Daqing 163000, China
References Godar, S.C., Bortolato, M., 2014. Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Frontiers in Behavioral Neuroscience 8, 71. Kishi, T., Fukuo, Y., Kitajima, T., Okochi, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., Inada, T., Kunugi, H., Kato, T., Yoshikawa, T., Ujike, H., Ozaki, N., Iwata, N., 2011. SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study. Genes, Brain and Behavior 10, 257–263. Ma, H., Huang, Y.L., Zhang, B., Li, J., Wang, Y., Zhao, X.F., Jin, Q., Zhu, G., 2013. Association between neurotensin receptor 1 (NTR1) gene polymorphisms and schizophrenia in a Han Chinese population. Journal of Molecular Neuroscience 50, 345–352. Park, G., Jeong, J.W., Kim, J.E., 2011. SIRT1 deficiency attenuates MPPþ -induced apoptosis in dopaminergic cells. The Federation of European Biochemical Societies letters 585, 219–224. Shuto, T., Kuroiwa, M., Koga, Y., Kawahara, Y., Sotogaku, N., Toyomasu, K., Nishi, A., 2013. Acute effects of resveratrol to enhance cocaine-induced dopamine neurotransmission in the striatum. Neuroscience Letters 542, 107–112.
Hui Ma Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China Center for Mental Health, Yanshan University, Qinhuangdao 066004, China Received 21 September 2014 Revised 12 November 2014 Accepted 16 November 2014 Available online 25 November 2014
n
Corresponding author.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Association between Silent Information Regulator 1 (SIRT1) gene polymorphisms and schizophrenia in a Chinese Han population To the Editors: Schizophrenia is a common mental illness with a complex etiology involving a multitude of susceptibility genes. Historically, the predominant explanation for schizophrenia has been the “dopamine hypothesis”, which states that genes involved in the dopaminergic signal transduction system contribute to the pathogenesis of schizophrenia and (or) to the expression of symptoms (Godar and Bortolato, 2014). Silent Information Regulator 1 (SIRT1) has been implicated in a variety of cellular functions, including circadian rhythms and dopaminergic signaling (Park et al., 2011; Shuto et al., 2013). A case-control study of Japanese schizophrenia and bipolar patients revealed an association between schizophrenia and two SIRT1 haplotypes involving four single nucleotide polymorphisms (SNPs) (Kishi et al., 2011). These results suggest that altered expression, mutations, and (or) polymorphisms of SIRT1 may be involved in the pathogenesis of schizophrenia. However, there are no studies testing such an association in the Chinese population. Here, we conducted a case-control study to investigate the association between four SIRT1 SNPs (rs3758391C/T, rs4746720C/T, rs10997875C/T and rs3740051A/G) and schizophrenia in Chinese Han subjects. We studied 376 unrelated schizophrenia patients (238 males and 138 females, mean age: 47.42 years, SD¼10.06, range, 20 72 years), and 569 healthy control subjects (271 males and 298 females, mean age: 32.14 years, SD¼7.77, range: 21 60 years). All were screened by experienced psychiatrists before collecting blood samples for genotyping. Clinical diagnosis was made independently by two senior psychiatrists based on structured interviews and a review of medical records following DSM–IV (American Psychiatric Association) criteria. The polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism analysis according to the methods described in our previous study (Ma et al., 2013). All the protocols were approved by the Ethics Committee of China Medical University. Allele frequencies and genotypes were estimated by the gene-counting method, and differences in distribution between cases and controls were tested using χ2 analysis or Fisher's test. We also performed linkage disequilibrium analysis and haplotype frequency comparison of the four polymorphisms using Haploview version 4.2. Allele, genotype and haplotype frequencies were also assessed separately for males and females. The SIRT1 genotype distribution of the control group was consistent with Hardy–Weinberg equilibrium (χ2 ¼0.253, 0.420, 0.711, 3.211; P¼0.615, 0.517, 0.399, 0.073, respectively). Compared with the healthy control subjects, the frequencies for AA genotypes (χ2 ¼ 22.891, P¼0.000) and A allele (χ2 ¼ 18.328, P¼ 0.000, OR¼ 0.608, 95% CI¼0.484–0.765) of the rs3740051A/G polymorphism were http://dx.doi.org/10.1016/j.psychres.2014.11.027 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
significantly higher in the schizophrenic patients (Table 1). And in gender-specific analyses, there were significant differences in the frequencies of the genotype (male: χ2 ¼ 11.575, P¼ 0.003; female: χ2 ¼11.903, P¼ 0.003) and allele (male: χ2 ¼ 9.810, P¼ 0.002, OR¼0.621, 95%CI¼0.460–0.838; female: χ2 ¼8.979, P¼ 0.003, OR¼0.574, 95%CI¼0.398–0.828) between the patients and controls (Table 1). In the whole study group, a strong pair-wise linkage disequilibrium of the SIRT1 gene was found among the four SNPs, and the same result was found when samples were divided by sex (all |D0 |40.85). The frequencies of the TGTT haplotype were significantly higher in the control subjects, while the CATT haplotype frequencies were significantly higher in the patients for both the whole subjects (χ2 ¼15.982, 11.358, P¼0.000, 0.001) and subjects grouped by gender (male: χ2 ¼9.712, 4.158, P¼0.002, 0.042; female: χ2 ¼10.615, 7.970, P¼ 0.001, 0.005). Additionally, we also observed higher TATT haplotype frequencies in the patients for both the whole subjects (χ2 ¼8.731, P¼ 0.003) and the female subjects (χ2 ¼5.347, P¼ 0.021). Our results suggest that the Chinese subjects carrying the A allele (AA genotype) of the rs3740051A/G polymorphism or the CATT and TATT haplotypes may be more at risk for schizophrenia, while subjects carrying the TGTT haplotype may have a reduced risk accordingly. The aforementioned Japanese study (Kishi et al., 2011) found an association between rs4746720 and schizophrenia, although the correlation was no longer significant after Bonferroni correction. Genetic heterogeneity between Chinese Han and Japanese populations as well as systematic differences in environments may account for the difference in the strength of the rs4746720 association between these populations. On the other hand, the significant association of two haplotypes of 4 SIRT1 SNPs (rs12778366T/C, rs2273773T/C, rs4746720T/C, and rs10997875T/ C; TTTT and TTCT) with schizophrenia in the Japanese cohort together with our result suggests that SIRT1 may be a promising susceptibility gene for schizophrenia. For the same chromosomal region or gene, however, the strength of the correlation can vary markedly among populations, so positive results in one ethnic population must be confirmed in others. Han Chinese account for a significant proportion of the world's total population, and for an approximately equivalent proportion of all schizophrenics. Therefore, the association analysis between the SIRT1 gene and schizophrenia in the Chinese Han population is of theoretical and practical significance. In conclusion, our results suggest an association between the SIRT1 gene and schizophrenia in the Chinese Han population, although the effects of the identified haplotype on regional SIRT1 expression and function remain to be determined. We speculate that this particular variant may disrupt circadian rhythms and (or) DA signaling, thereby contributing to disease pathogenesis and (or) expression. However, further studies are required to replicate in different ethnic groups. Furthermore, schizophrenia is a polygenic disease, so large samples are required to reveal the minor effects of single genes. Nonetheless, this study provides further evidence that allelic variants of SIRT1 contribute to schizophrenia risk, at least in Asian populations.
Letter to the Editor / Psychiatry Research 225 (2015) 744–745
745
Table 1 Genotype and allele distribution of the four analyzed SNPs in schizophrenia patients and controls. SNP
Patient, n(%)
Controls, χ2 n (%)
P
OR (95%CI)
rs3758391 Genotypes CC 21(5.6) 16(2.8) CT 89(23.7) 149(26.2) TT 266(70.7) 404(71.0) 5.018 0.081 Alleles C 131(17.4) 181(15.9) T 621(82.6) 957(84.1) 0.754 0.385 1.115 (0.872– 1.427) rs4746720 Genotypes CC 77(20.5) 105(18.5) CT 178(47.3) 270(47.4) TT 121(32.2) 194(34.1) 0.732 0.694 Alleles C 332(4414) 480(42.2) T 420(55.9) 658(57.8) 0.717 0.397 1.084 (0.900– 1.305) rs10997875 Genotypes CC 5(1.3) 12(2.1) CT 110(29.3) 159(28.0) TT 261(69.4) 398(69.9) 0.910 0.634 Alleles C 120(16.0) 183(16.1) T 632(84.0) 955(83.9) 0.005 0.943 0.991 (0.771– 1.274) rs3740051 Genotypes GG AG AA Alleles G A
a
Male Male Patients, n(%) Controls, n (%)
13(5.5) 58(24.4) 167(70.2)
7(2.6) 70(25.8) 194(71.6)
84(17.6) 392(82.4)
84(15.5) 458(84.5)
46(19.3) 117(49.2) 75(31.5)
45(16.6) 136(50.2) 90(33.2)
209(43.9) 267(56.1)
226(41.7) 316(58.3)
3(1.3) 69(29.0) 166(69.7)
5(1.8) 75(27.7) 191(70.5)
75(15.8) 401(84.2)
85(15.7) 457(84.3)
3(1.3) 82(34.5) 153(64.3)
12(4.4) 121(44.7) 138(50.9)
134(17.8) 299(26.3) 88(18.5) 618(82.2) 839(73.7) 18.328 0.000a 0.608 (0.484– 388(81.5) 0.765)
145(26.8) 397(73.2)
3(0.8) 31(5.4) 128(34.0) 237(41.7) 245(65.2) 301(52.9) 22.891 0.000a
χ2
P
2.817 0.245
OR (95%CI)
Female Female χ2 Patients, n(%) Controls, n (%)
8(5.8) 31(22.5) 99(71.7)
47(17.0) 0.849 0.357 1.168 (0.839– 229(83.0) 1.627)
0.665 0.717
31(22.5) 61(44.2) 46(33.3)
123(44.6) 0.506 0.477 1.094 (0.853– 153(55.4) 1.404)
0.363 0.834
2(1.4) 41(29.7) 95(68.9)
45(16.3) 0.001 0.974 1.006 (0.717– 231(83.7) 1.410)
11.575 0.00a
0(0.0) 46(33.3) 92(66.7)
46(16.7) 9.810 0.002a 0.621 (0.460– 230(83.3) 0.838)
9(3.0) 79(26.5) 210(70.5) 97(16.3) 499(83.7)
60(20.1) 134(45.0) 104(34.9) 254(42.6) 342(57.4)
7(2.3) 84(28.2) 207(69.5) 98(16.4) 498(83.6)
19(6.4) 116(38.9) 163(54.7) 154(25.8) 442(74.2)
P
OR (95%CI)
2.499 0.287
0.078 0.780 1.056 (0.721–1.54)
0.325 0.850
0.292 0.589 1.082(0.812– 1.443)
0.451 0.798
0.003 0.959 0.990 (0.673– 1.456)
11.903 0.003a
8.979 0.003a 0.574 (0.398– 0.828)
P o0.05 is taken to indicate statistical significance.
Conflict of interest
Yuan Wang, Yinglin Huang, Miao Peng Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China Department of Psychology, Shengjing Hospital of China Medical University, Shenyang 110022, China
All authors declare that they have no conflicts of interest. Acknowledgments
Zhengtu Cong, Xin Li, Ailu Lin, Gang Zhu n Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China E-mail address: [email protected] (G. Zhu)
This study was supported by a grant from a project of Liaoning SHIBAIQIAN high-end talent, a grant from Liaoning Science & Technology project (2011408004), and a grant from National Natural Science Foundation of China (81271442) for Prof. Gang Zhu.
Longyan Peng The Third Hospital of Daqing, Daqing 163000, China
References Godar, S.C., Bortolato, M., 2014. Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission. Frontiers in Behavioral Neuroscience 8, 71. Kishi, T., Fukuo, Y., Kitajima, T., Okochi, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., Inada, T., Kunugi, H., Kato, T., Yoshikawa, T., Ujike, H., Ozaki, N., Iwata, N., 2011. SIRT1 gene, schizophrenia and bipolar disorder in the Japanese population: an association study. Genes, Brain and Behavior 10, 257–263. Ma, H., Huang, Y.L., Zhang, B., Li, J., Wang, Y., Zhao, X.F., Jin, Q., Zhu, G., 2013. Association between neurotensin receptor 1 (NTR1) gene polymorphisms and schizophrenia in a Han Chinese population. Journal of Molecular Neuroscience 50, 345–352. Park, G., Jeong, J.W., Kim, J.E., 2011. SIRT1 deficiency attenuates MPPþ -induced apoptosis in dopaminergic cells. The Federation of European Biochemical Societies letters 585, 219–224. Shuto, T., Kuroiwa, M., Koga, Y., Kawahara, Y., Sotogaku, N., Toyomasu, K., Nishi, A., 2013. Acute effects of resveratrol to enhance cocaine-induced dopamine neurotransmission in the striatum. Neuroscience Letters 542, 107–112.
Hui Ma Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, China Center for Mental Health, Yanshan University, Qinhuangdao 066004, China Received 21 September 2014 Revised 12 November 2014 Accepted 16 November 2014 Available online 25 November 2014
n
Corresponding author.
