J Neural Transm DOI 10.1007/s00702-014-1348-2
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
TSNARE1 polymorphisms are associated with schizophrenia susceptibility in Han Chinese Li-Ze Gu • Teng Jiang • Zao-Huo Cheng Yue-Chun Zhang • Meng-Meng Ou • Min-Chi Chen • Wei-Ming Ling
•
Received: 11 August 2014 / Accepted: 30 November 2014 Ó Springer-Verlag Wien 2014
Abstract t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a crucial role in intracellular protein transport and synaptic transmission. Recently, a large-scale meta-analysis of genome-wide association study dataset identified that rs10098073 and rs4129585, two single nucleotide polymorphisms (SNPs) within TSNARE1, were closely associated with the risk of schizophrenia in Caucasians. However, this finding has not been validated in other populations or ethnic groups thus far. In the current study, we conducted a case-control study to confirm the association of these two SNPs with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D0 = 1, r2 C 0.952). Therefore, only rs10098073 was selected for the subsequent analysis. We showed for the first time that the minor allele (A) of rs10098073 was associated with a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613–0.924; P = 0.007). Furthermore, we found that the A allele of rs10098073 reduced the schizophrenia risk through
L.-Z. Gu T. Jiang (&) Y.-C. Zhang M.-M. Ou M.-C. Chen W.-M. Ling (&) Department of Laboratory Medicine, Wuxi Mental Health Center, Nanjing Medical University, No. 156, Qian Rong Road, Wuxi, China e-mail: [email protected] W.-M. Ling e-mail: [email protected] T. Jiang Z.-H. Cheng Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
a recessive manner (A/A vs. A/C ? C/C, OR = 0.563; 95 % CI 0.357–0.89; P = 0.013, PBonferroni corrected = 0.026) rather than a dominant manner (A/A ? A/C vs. C/C, OR = 0.762; 95 % CI 0.586–0.992; P = 0.043, PBonferroni corrected = 0.086). Taken together, these findings demonstrate a significant association between TSNARE1 polymorphisms and schizophrenia risk in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease. Keywords Schizophrenia TSNARE1 Single nucleotide polymorphism Han Chinese Association
Introduction As a devastating psychiatric disorder with a median lifetime prevalence rate of approximately 1 %, schizophrenia is commonly manifested by auditory hallucinations, paranoid or bizarre delusions, altered emotional reactivity and disorganized behaviors (Perala et al. 2007; Prince et al. 2007). Although the precise etiology of schizophrenia remains still unclear, genetic components have been proved to be the strongest risk factors for this disorder (Allan et al. 2008; Ivleva et al. 2008). In recent years, several genomewide association studies (GWAS) have been conducted in Caucasian populations. Using this effective strategy, numerous susceptibility loci and risk genes including ITIH3/4, CACNA1C, SDCCAG8, CSMD1/2, ZKSCAN4 and NKAPL have been identified, which greatly advanced our understanding of the etiology and pathogenesis underlying schizophrenia (Hamshere et al. 2013; Havik et al. 2011; Ripke et al. 2013; Yue et al. 2011). t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a
123
L.-Z. Gu et al.
crucial role in intracellular protein transport and synaptic transmission (Smith et al. 2012). Interestingly, a recent large-scale meta-analysis of GWAS involving schizophrenia patients of Caucasian ancestry identified that rs10098073 and rs4129585, two SNPs within TSNARE1, were closely associated with the risk of schizophrenia (Sleiman et al. 2013). However, this association needs to be confirmed in other ethnic groups and population, including Han Chinese. Therefore, the aim of the current study was to validate the relation between these two SNPs and schizophrenia susceptibility in an independent Han Chinese population including 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D0 = 1, r2 C 0.952). Therefore, only rs10098073 was selected for the subsequent analysis.
Materials and methods Subjects This study was conducted in accordance with the Declaration of Helsinki, and written informed consents were obtained from participants or their guardians. Meanwhile, all procedures for this study were approved by the Institutional Review Boards of the Wuxi Mental Health Center. The study included 440 schizophrenia patients and 450 control subjects. All the subjects were of Han Chinese origin and unrelated to each other. The patients were recruited from inpatient units of Wuxi Mental Health Center as described (Gu et al. 2014; Jin et al. 2014, 2013): (a) patients met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and the diagnoses were made based on the Structured Clinical Interview for DSM-IV-TR Axis I Disorders; (b) first-episode patients were not involved since initial diagnoses are often unreliable; and (c) patients had no physical disease, neurological disease or other psychiatric disorder aside from schizophrenia. Diagnosis and review of psychiatric case records were performed by two or more senior psychiatrists. The control subjects were recruited among the staffs from Nanjing Medical University and Wuxi Mental Health Center who had been examined by two experienced psychiatrists. It is worthy to note that subjects with chronic physical diseases or psychiatric disorders were excluded from this study.
123
DNA extraction and SNP genotyping The peripheral blood samples of schizophrenia patients and control subjects were collected using anticoagulant tubes. Genomic DNA was extracted from leukocytes using the Wizard genomic DNA purification kit (#A1125, Promega, USA) as described (Jiang et al. 2014a, b; Lu et al. 2014; Tan et al. 2014; Yu et al. 2014). Genotyping of rs10098073 was carried out by polymerase chain reaction-ligase detection reaction on ABI Prism 377 sequence detection system as described. Data were analyzed by GeneMapper Software version 4.0. Randomly selected DNA samples from each genotype were analyzed in duplicate using ligation detection reaction and sequence analysis. Consistent results were obtained by these two methods, and the genotype call rates in patients and control subjects were [99 %. Statistical analysis The statistical power of this study was determined using STPLAN version 4.3 software under a given sample size and significance level (a = 0.05). Hardy–Weinberg equilibrium (HWE) analysis was performed in control subjects using HWE calculator version 1.20. The genotype and allele distributions in schizophrenia patients and control subjects were compared by the v2 test or Fisher’s exact test, and the P value, odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using Stata software version 12.0. P \ 0.05 was considered statistically significant.
Results This study contained a total of 890 subjects including 440 schizophrenia patients and 450 control subjects. As indicated by Table 1, there were no statistically significant differences in age and gender between schizophrenia patients and control subjects. Meanwhile, in our control group, the distribution of rs10098073 was in HWE (P = 0.074), and the genotype and allele frequencies of rs10098073 were in accordance with CHB genotype data in 1,000 Genomes Project database (See Table 2). As shown by Table 3, the genotype and allele frequencies of rs10098073 in schizophrenia patients were significantly different from those in control subjects (Pgenotype = 0.021, Pallele = 0.007). More importantly, the presence of minor allele (A) of rs10098073 led to a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613–0.924; P = 0.007) in our cohort. Afterward, we further analyzed the association of rs10098073 with schizophrenia risk under different genetic models. As indicated by Table 4, the A allele of rs10098073
TSNARE1 polymorphisms are associated with schizophrenia Table 1 Characteristics of our samples Characteristic
Schizophrenia patients (n = 440)
Control subjects (n = 450)
P value
Age, years (mean ± SD)
41.75 ± 9
42.61 ± 9.64
0.171
Age range, years
22–63
23–66
Age at onset, years (mean ± SD)
27.52 ± 4.56
Gender, n (%) Male
252 (57 %)
275 (61 %)
Female
188 (43 %)
175 (39 %)
0.244
reduced the schizophrenia risk through a recessive manner (A/A vs. A/C ? C/C, OR = 0.563; 95 % CI 0.357–0.89; P = 0.013, PBonferroni corrected = 0.026) rather than a dominant manner (A/A ? A/C vs. C/C, OR = 0.762; 95 % CI 0.586–0.992; P = 0.043, PBonferroni corrected = 0.086). It is worthy to note that the current study offered a[75 % power to detect an OR = 0.75 with a = 0.05, which is sufficient enough to draw a conclusion on the association between rs10098073 and the schizophrenia susceptibility in our cohort.
Discussion In the current study, we carried out a case-control study to investigate the association between TSNARE1 polymorphisms and schizophrenia susceptibility in a Han Chinese population. We provided the first evidence that the minor allele of rs10098073 was significantly associated with a reduced risk of schizophrenia in Han Chinese, confirming
Table 2 Comparison of genotypes and allele frequencies of rs10098073 between our control subjects and those obtained from the 1,000 Genomes Project database
Samples
n
Genotypes n (%) A/A
1,000 Genomes Project data Our control subjects
the results from a recent large-scale meta-analysis of Caucasian GWAS data (Sleiman et al. 2013). Interestingly, in Caucasian, rs10098073 also closely associated with the risk of bipolar disorder, another severe psychiatric disorder (Sleiman et al. 2013). These genetic findings indicated that TSNARE1 represented a shared susceptibility factor for these two psychiatric diseases, and was likely to play an important role in the pathogenesis of them. However, the biological function of TSNARE1 remains largely unknown thus far. A recent study from Smith and colleagues suggested that TSNARE1 might have evolved within the vertebrate lineage from the harbinger transposon superfamily (Smith et al. 2012). Bioinformatic predictions based on phylogenetic ancestry indicated that TSNARE1 might bind soluble N-ethylmaleimide-sensitive factor attached protein (SNAP) receptor proteins and possess SNAP receptor activity (Smith et al. 2012). Hence, TSNARE1 was presumed to have a vertebrate-specific function in intracellular protein transport and synaptic transmission. In future, the precise function of TSNARE1 and its role in the pathogenesis of schizophrenia as well as bipolar disorder should be investigated. Meanwhile, the underlying mechanisms by which rs10098073 affected the risk of schizophrenia and bipolar disorder should also be determined. In conclusion, this study provides the first evidence that the minor allele of rs10098073, a SNP within TSNARE1, is significantly associated with a reduced risk of schizophrenia in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease. These findings require further validation in a larger Han Chinese cohort as well as in other racial and ethnic groups. Meanwhile, in-depth analyses on the association of rs10098073 with clinical characteristics of schizophrenia
97
11 (11.3)
450
55 (12.2)
Alleles n (%)
A/C
C/C
35 (36.1) 180 (40)
P value
51 (52.6)
0.69
215 (47.8)
A
C
P value
54 (29.4)
137 (70.6)
0.286
290 (32.2)
610 (67.8)
Table 3 Distribution of rs10098073 in schizophrenia patients and control subjects n
Genotypes n (%) A/A
A/C
Alleles n (%) C/C
P value 0.021
Schizophrenia patients
440
32 (7.3)
168 (38.2)
240 (54.5)
Control subjects
450
55 (12.2)
180 (40)
215 (47.8)
A
C
P value
OR (95 % CI)
232 (26.4)
648 (73.6)
0.007
0.753 (0.613–0.924)*
290 (32.2)
610 (67.8)
CI confidence interval, OR odds ratio * Power = 0.751, calculated by the STPLAN version 4.3 software under a given sample size and significance level (a = 0.05)
123
L.-Z. Gu et al. Table 4 Association of rs10098073 with schizophrenia risk under different genetic models Model#
OR (95 % CI)
P value
Pc value
Dominant
0.762 (0.586–0.992)
0.043
0.086 (NS)
Recessive
0.563 (0.357–0.890)
0.013
0.026
CI confidence interval, NS non-significance, OR odds ratio, Pc, P value after Bonferroni correction #
The genetic models were defined as follows: (A/A ? A/C) versus C/C for dominant model and A/A versus (A/C ? C/C) for recessive model
such as positive symptoms, negative symptoms and neurocognitive functions are urgently needed. In addition, since rs10098073 is closely associated with susceptibility of bipolar disorder in Caucasians, it is also necessary to test this association in Chinese patients with bipolar disorder in the future. Acknowledgments This work was supported by the Innovation Project for Postgraduates of Jiangsu Province to T.J. (CXLX13_561) and the Foundation of Nanjing Medical University for Development of Science and Technology to L-Z.G. (2014NJMU114). Conflict of interest
The authors declare no conflict of interest.
References Allan CL, Cardno AG, McGuffin P (2008) Schizophrenia: from genes to phenes to disease. Curr Psychiatry Rep 10:339–343 Gu LZ et al (2014) rs11098403 polymorphism near NDST3 is associated with a reduced risk of schizophrenia in a Han Chinese population. Neurosci Lett 581:42–45. doi:10.1016/j.neulet.2014. 08.018 Hamshere ML et al (2013) Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 18:708–712. doi:10.1038/mp. 2012.67 Havik B et al (2011) The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry 70:35–42. doi:10.1016/j.biopsych.2011.01.030
123
Ivleva E, Thaker G, Tamminga CA (2008) Comparing genes and phenomenology in the major psychoses: schizophrenia and bipolar 1 disorder. Schizophr Bull 34:734–742. doi:10.1093/ schbul/sbn051 Jiang T et al (2014) Genetic variation in PICALM and Alzheimer’s disease risk in Han Chinese. Neurobiol Aging 35:934.e1–934.e3. doi:10.1016/j.neurobiolaging.2013.09.014 Jiang T et al (2014b) The Genetic Variation of ARRB2 is associated with Late-Onset Alzheimer’s Disease in Han Chinese current Alzheimer research Jin C et al (2013) Lack of association between MPC2 variants and schizophrenia in a replication study of Han Chinese. Neurosci Lett 552:120–123. doi:10.1016/j.neulet.2013.07.051 Jin C et al (2014) The SORL1 polymorphism rs985421 may confer the risk for amnestic mild cognitive impairment and Alzheimer’s disease in the Han Chinese population. Neurosci Lett 563:80–84. doi:10.1016/j.neulet.2014.01.029 Lu RC, Wang H, Tan MS, Yu JT, Tan L (2014) TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer’s disease in Han Chinese. J Neural Transm 121:283–287. doi:10.1007/s00702-013-1106-x Perala J et al (2007) Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry 64:19–28. doi:10.1001/archpsyc.64.1.19 Prince M, Patel V, Saxena S, Maj M, Maselko J, Phillips MR, Rahman A (2007) No health without mental health. Lancet 370:859–877. doi:10.1016/S0140-6736(07)61238-0 Ripke S et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45:1150–1159. doi:10.1038/ng.2742 Sleiman P et al (2013) GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia/bipolar susceptibility locus scientific reports 3:3075 doi:10.1038/srep03075 Smith JJ, Sumiyama K, Amemiya CT (2012) A living fossil in the genome of a living fossil: Harbinger transposons in the coelacanth genome. Mol Biol Evol 29:985–993. doi:10.1093/ molbev/msr267 Tan MS, Yu JT, Jiang T, Zhu XC, Guan HS, Tan L (2014) Genetic variation in BIN1 gene and Alzheimer’s disease risk in Han Chinese individuals. Neurobiol Aging 35:1781.e1–1781.e8. doi:10.1016/j.neurobiolaging.2014.01.151 Yu JT et al (2014) Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer’s disease in Han Chinese individuals. Neurobiol Aging 35:937.e1–937.e3. doi:10.1016/j. neurobiolaging.2013.10.075 Yue WH et al (2011) Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet 43:1228–1231. doi:10.1038/ng.979
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
TSNARE1 polymorphisms are associated with schizophrenia susceptibility in Han Chinese Li-Ze Gu • Teng Jiang • Zao-Huo Cheng Yue-Chun Zhang • Meng-Meng Ou • Min-Chi Chen • Wei-Ming Ling
•
Received: 11 August 2014 / Accepted: 30 November 2014 Ó Springer-Verlag Wien 2014
Abstract t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a crucial role in intracellular protein transport and synaptic transmission. Recently, a large-scale meta-analysis of genome-wide association study dataset identified that rs10098073 and rs4129585, two single nucleotide polymorphisms (SNPs) within TSNARE1, were closely associated with the risk of schizophrenia in Caucasians. However, this finding has not been validated in other populations or ethnic groups thus far. In the current study, we conducted a case-control study to confirm the association of these two SNPs with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D0 = 1, r2 C 0.952). Therefore, only rs10098073 was selected for the subsequent analysis. We showed for the first time that the minor allele (A) of rs10098073 was associated with a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613–0.924; P = 0.007). Furthermore, we found that the A allele of rs10098073 reduced the schizophrenia risk through
L.-Z. Gu T. Jiang (&) Y.-C. Zhang M.-M. Ou M.-C. Chen W.-M. Ling (&) Department of Laboratory Medicine, Wuxi Mental Health Center, Nanjing Medical University, No. 156, Qian Rong Road, Wuxi, China e-mail: [email protected] W.-M. Ling e-mail: [email protected] T. Jiang Z.-H. Cheng Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
a recessive manner (A/A vs. A/C ? C/C, OR = 0.563; 95 % CI 0.357–0.89; P = 0.013, PBonferroni corrected = 0.026) rather than a dominant manner (A/A ? A/C vs. C/C, OR = 0.762; 95 % CI 0.586–0.992; P = 0.043, PBonferroni corrected = 0.086). Taken together, these findings demonstrate a significant association between TSNARE1 polymorphisms and schizophrenia risk in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease. Keywords Schizophrenia TSNARE1 Single nucleotide polymorphism Han Chinese Association
Introduction As a devastating psychiatric disorder with a median lifetime prevalence rate of approximately 1 %, schizophrenia is commonly manifested by auditory hallucinations, paranoid or bizarre delusions, altered emotional reactivity and disorganized behaviors (Perala et al. 2007; Prince et al. 2007). Although the precise etiology of schizophrenia remains still unclear, genetic components have been proved to be the strongest risk factors for this disorder (Allan et al. 2008; Ivleva et al. 2008). In recent years, several genomewide association studies (GWAS) have been conducted in Caucasian populations. Using this effective strategy, numerous susceptibility loci and risk genes including ITIH3/4, CACNA1C, SDCCAG8, CSMD1/2, ZKSCAN4 and NKAPL have been identified, which greatly advanced our understanding of the etiology and pathogenesis underlying schizophrenia (Hamshere et al. 2013; Havik et al. 2011; Ripke et al. 2013; Yue et al. 2011). t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a
123
L.-Z. Gu et al.
crucial role in intracellular protein transport and synaptic transmission (Smith et al. 2012). Interestingly, a recent large-scale meta-analysis of GWAS involving schizophrenia patients of Caucasian ancestry identified that rs10098073 and rs4129585, two SNPs within TSNARE1, were closely associated with the risk of schizophrenia (Sleiman et al. 2013). However, this association needs to be confirmed in other ethnic groups and population, including Han Chinese. Therefore, the aim of the current study was to validate the relation between these two SNPs and schizophrenia susceptibility in an independent Han Chinese population including 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D0 = 1, r2 C 0.952). Therefore, only rs10098073 was selected for the subsequent analysis.
Materials and methods Subjects This study was conducted in accordance with the Declaration of Helsinki, and written informed consents were obtained from participants or their guardians. Meanwhile, all procedures for this study were approved by the Institutional Review Boards of the Wuxi Mental Health Center. The study included 440 schizophrenia patients and 450 control subjects. All the subjects were of Han Chinese origin and unrelated to each other. The patients were recruited from inpatient units of Wuxi Mental Health Center as described (Gu et al. 2014; Jin et al. 2014, 2013): (a) patients met the criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and the diagnoses were made based on the Structured Clinical Interview for DSM-IV-TR Axis I Disorders; (b) first-episode patients were not involved since initial diagnoses are often unreliable; and (c) patients had no physical disease, neurological disease or other psychiatric disorder aside from schizophrenia. Diagnosis and review of psychiatric case records were performed by two or more senior psychiatrists. The control subjects were recruited among the staffs from Nanjing Medical University and Wuxi Mental Health Center who had been examined by two experienced psychiatrists. It is worthy to note that subjects with chronic physical diseases or psychiatric disorders were excluded from this study.
123
DNA extraction and SNP genotyping The peripheral blood samples of schizophrenia patients and control subjects were collected using anticoagulant tubes. Genomic DNA was extracted from leukocytes using the Wizard genomic DNA purification kit (#A1125, Promega, USA) as described (Jiang et al. 2014a, b; Lu et al. 2014; Tan et al. 2014; Yu et al. 2014). Genotyping of rs10098073 was carried out by polymerase chain reaction-ligase detection reaction on ABI Prism 377 sequence detection system as described. Data were analyzed by GeneMapper Software version 4.0. Randomly selected DNA samples from each genotype were analyzed in duplicate using ligation detection reaction and sequence analysis. Consistent results were obtained by these two methods, and the genotype call rates in patients and control subjects were [99 %. Statistical analysis The statistical power of this study was determined using STPLAN version 4.3 software under a given sample size and significance level (a = 0.05). Hardy–Weinberg equilibrium (HWE) analysis was performed in control subjects using HWE calculator version 1.20. The genotype and allele distributions in schizophrenia patients and control subjects were compared by the v2 test or Fisher’s exact test, and the P value, odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using Stata software version 12.0. P \ 0.05 was considered statistically significant.
Results This study contained a total of 890 subjects including 440 schizophrenia patients and 450 control subjects. As indicated by Table 1, there were no statistically significant differences in age and gender between schizophrenia patients and control subjects. Meanwhile, in our control group, the distribution of rs10098073 was in HWE (P = 0.074), and the genotype and allele frequencies of rs10098073 were in accordance with CHB genotype data in 1,000 Genomes Project database (See Table 2). As shown by Table 3, the genotype and allele frequencies of rs10098073 in schizophrenia patients were significantly different from those in control subjects (Pgenotype = 0.021, Pallele = 0.007). More importantly, the presence of minor allele (A) of rs10098073 led to a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613–0.924; P = 0.007) in our cohort. Afterward, we further analyzed the association of rs10098073 with schizophrenia risk under different genetic models. As indicated by Table 4, the A allele of rs10098073
TSNARE1 polymorphisms are associated with schizophrenia Table 1 Characteristics of our samples Characteristic
Schizophrenia patients (n = 440)
Control subjects (n = 450)
P value
Age, years (mean ± SD)
41.75 ± 9
42.61 ± 9.64
0.171
Age range, years
22–63
23–66
Age at onset, years (mean ± SD)
27.52 ± 4.56
Gender, n (%) Male
252 (57 %)
275 (61 %)
Female
188 (43 %)
175 (39 %)
0.244
reduced the schizophrenia risk through a recessive manner (A/A vs. A/C ? C/C, OR = 0.563; 95 % CI 0.357–0.89; P = 0.013, PBonferroni corrected = 0.026) rather than a dominant manner (A/A ? A/C vs. C/C, OR = 0.762; 95 % CI 0.586–0.992; P = 0.043, PBonferroni corrected = 0.086). It is worthy to note that the current study offered a[75 % power to detect an OR = 0.75 with a = 0.05, which is sufficient enough to draw a conclusion on the association between rs10098073 and the schizophrenia susceptibility in our cohort.
Discussion In the current study, we carried out a case-control study to investigate the association between TSNARE1 polymorphisms and schizophrenia susceptibility in a Han Chinese population. We provided the first evidence that the minor allele of rs10098073 was significantly associated with a reduced risk of schizophrenia in Han Chinese, confirming
Table 2 Comparison of genotypes and allele frequencies of rs10098073 between our control subjects and those obtained from the 1,000 Genomes Project database
Samples
n
Genotypes n (%) A/A
1,000 Genomes Project data Our control subjects
the results from a recent large-scale meta-analysis of Caucasian GWAS data (Sleiman et al. 2013). Interestingly, in Caucasian, rs10098073 also closely associated with the risk of bipolar disorder, another severe psychiatric disorder (Sleiman et al. 2013). These genetic findings indicated that TSNARE1 represented a shared susceptibility factor for these two psychiatric diseases, and was likely to play an important role in the pathogenesis of them. However, the biological function of TSNARE1 remains largely unknown thus far. A recent study from Smith and colleagues suggested that TSNARE1 might have evolved within the vertebrate lineage from the harbinger transposon superfamily (Smith et al. 2012). Bioinformatic predictions based on phylogenetic ancestry indicated that TSNARE1 might bind soluble N-ethylmaleimide-sensitive factor attached protein (SNAP) receptor proteins and possess SNAP receptor activity (Smith et al. 2012). Hence, TSNARE1 was presumed to have a vertebrate-specific function in intracellular protein transport and synaptic transmission. In future, the precise function of TSNARE1 and its role in the pathogenesis of schizophrenia as well as bipolar disorder should be investigated. Meanwhile, the underlying mechanisms by which rs10098073 affected the risk of schizophrenia and bipolar disorder should also be determined. In conclusion, this study provides the first evidence that the minor allele of rs10098073, a SNP within TSNARE1, is significantly associated with a reduced risk of schizophrenia in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease. These findings require further validation in a larger Han Chinese cohort as well as in other racial and ethnic groups. Meanwhile, in-depth analyses on the association of rs10098073 with clinical characteristics of schizophrenia
97
11 (11.3)
450
55 (12.2)
Alleles n (%)
A/C
C/C
35 (36.1) 180 (40)
P value
51 (52.6)
0.69
215 (47.8)
A
C
P value
54 (29.4)
137 (70.6)
0.286
290 (32.2)
610 (67.8)
Table 3 Distribution of rs10098073 in schizophrenia patients and control subjects n
Genotypes n (%) A/A
A/C
Alleles n (%) C/C
P value 0.021
Schizophrenia patients
440
32 (7.3)
168 (38.2)
240 (54.5)
Control subjects
450
55 (12.2)
180 (40)
215 (47.8)
A
C
P value
OR (95 % CI)
232 (26.4)
648 (73.6)
0.007
0.753 (0.613–0.924)*
290 (32.2)
610 (67.8)
CI confidence interval, OR odds ratio * Power = 0.751, calculated by the STPLAN version 4.3 software under a given sample size and significance level (a = 0.05)
123
L.-Z. Gu et al. Table 4 Association of rs10098073 with schizophrenia risk under different genetic models Model#
OR (95 % CI)
P value
Pc value
Dominant
0.762 (0.586–0.992)
0.043
0.086 (NS)
Recessive
0.563 (0.357–0.890)
0.013
0.026
CI confidence interval, NS non-significance, OR odds ratio, Pc, P value after Bonferroni correction #
The genetic models were defined as follows: (A/A ? A/C) versus C/C for dominant model and A/A versus (A/C ? C/C) for recessive model
such as positive symptoms, negative symptoms and neurocognitive functions are urgently needed. In addition, since rs10098073 is closely associated with susceptibility of bipolar disorder in Caucasians, it is also necessary to test this association in Chinese patients with bipolar disorder in the future. Acknowledgments This work was supported by the Innovation Project for Postgraduates of Jiangsu Province to T.J. (CXLX13_561) and the Foundation of Nanjing Medical University for Development of Science and Technology to L-Z.G. (2014NJMU114). Conflict of interest
The authors declare no conflict of interest.
References Allan CL, Cardno AG, McGuffin P (2008) Schizophrenia: from genes to phenes to disease. Curr Psychiatry Rep 10:339–343 Gu LZ et al (2014) rs11098403 polymorphism near NDST3 is associated with a reduced risk of schizophrenia in a Han Chinese population. Neurosci Lett 581:42–45. doi:10.1016/j.neulet.2014. 08.018 Hamshere ML et al (2013) Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 18:708–712. doi:10.1038/mp. 2012.67 Havik B et al (2011) The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry 70:35–42. doi:10.1016/j.biopsych.2011.01.030
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