Effects of the Adverse Life Events and Disrupted in Schizophrenia-1 ( DISC1 ) Gene Polymorphisms on Acute Symptoms of Schizophrenia

Abstract

The aim of this study was to evaluate the effects of traumatic childhood events and recent adverse life events, as well as the Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on types of last acute symptoms of patients with schizophrenia. Hundred patients with schizophrenia were given the Childhood Trauma Questionnaire, the Social Readjustment Rating Scale, Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), and Calgary Depression Scale for Schizophrenia (CDSS). The patients' and healthy controls' DISC1 gene was evaluated for the −274G>C, c.791G>A, and c.2110A>T polymorphisms. There was no statistically significant difference with regard to the DISC1 gene polymorphisms between patient and healthy control groups. No significant relationship was found between the −274G>C, c.791G>A, and c.2110A>T haplotypes and development of different acute symptoms of schizophrenia. Having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=−67.547, −21.473; p=0.00) and BPRS-1 scores (95% CI=−51.405, −6.885; p=0.01), whereas emotional abuse at childhood significantly affected SANS scores (95% CI=−37.300, −10.401; p=0.00). This study shows that features of acute symptoms in schizophrenia are not influenced by the polymorphisms on the DISC1 gene, but are influenced by recent adverse life events and emotional abuse at childhood.

Introduction

D escribing specific environmental and genetic risk factors for schizophrenia has great importance for early intervention in psychiatry. Schizophrenia is well known to have a genetic basis. Yet, concordance of schizophrenia is never 100% for monozygotic twins, and never 50% for dizygotic twins. This fact shows that environmental factors also play a major role in the development of schizophrenia (van Os and Marcelis, 1998). A number of environmental risk factors for development of schizophrenia have been identified. The earliest of these are complications of pregnancy and birth, while late environmental risk factors have been identified as immigrant status, chronic cannabis abuse, and adverse life events (McDonald and Murray, 2000). Many studies have reported an excess of stressful life events in the few weeks before the onset or relapse of schizophrenia (Day et al., 1987; Ventura et al., 1989; Malla et al., 1990; Hirsch et al., 1996). The fine-tuning of the brain connections under the influence of stress and hormones may ultimately lead to neurodegeneration, loss of brain mass, and overt psychosis (Tsuang, 2000).

Genetic and linkage studies of schizophrenia have especially focused on genes that control neurodevelopment. Among these genes, Disrupted in Schizophrenia-1 (DISC1) has been one of the most promising candidates. Human DISC1 is a large gene containing 13 exons spanning over 410 kilo base pairs of genomic DNA (Millar et al., 2000). Within the brain, expression is strongest in the hippocampus within the granule cells of the dentate gyrus and pyramidal cells (James et al., 2004). It is suggested that DISC1 has a role in corticogenesis and synaptic remodeling, again consistent with the high expression of DISC1 in the dentate gyrus and the olfactory bulb, as these are sites of adult neurogenesis (Cayre et al., 2002). Importantly, evidence is emerging from genetic studies for a causal relationship between DISC1 and directly measurable trait variables such as working memory (Gasperoni et al., 2003; Hennah et al., 2005; Burdick et al., 2005), cognitive aging (Callicott et al., 2005; Thomson et al., 2005b), decreased gray matter volume in the prefrontal cortex (Cannon et al., 2005), and abnormalities in the hippocampal structure and function (Cayre et al., 2002). Thus, both genetic and functional data provide evidence for a critical role for DISC1 in neurodevelopment.

The DISC1 gene was implicated through studies of an extended pedigree in which a balanced chromosomal translocation (1;11) (q42;q14.3) showed strong evidence for linkage to a fairly broad phenotype comprising schizophrenia, bipolar disorder, and recurrent depression (Blackwood et al., 2001). Negative studies in schizophrenia samples were initially reported by the Edinburgh group with a small number of markers (Devon et al., 2002) and by a group who focused on the 5′-end of the gene in a large Japanese sample (Kockelkorn et al., 2004). More recently, several groups have reported positive findings (Hennah et al., 2003; Hodgkinson et al., 2004; Callicott et al., 2005; Thomson et al., 2005; Palo et al., 2007; Qu et al., 2007; Kim et al., 2008; Saetre et al., 2008; Schumacher et al., 2009; Tomppo et al., 2009; Chakirova et al., 2011; Shaikh et al., 2011; Wei et al., 2012).

In this study, we aimed to find the collaborative effects of the DISC1 gene and environmental factors, such as childhood adverse events and recent stressful life events, on different symptom clusters of schizophrenia, namely, positive, negative, and depressive symptoms.

Materials and Methods

Subjects

About 100 patients with schizophrenia and 100 healthy controls were included in this study. All the subjects signed a written informed consent form before inclusion to the study. Ethics approval of this was given by the Gazi University Local Ethics Committee.

Patients with schizophrenia were chosen among patients who have admitted to outpatient and inpatient psychiatry units of the Gazi University Hospital. Schizophrenia diagnosis was confirmed by using the semistructured clinical interview for DSM-IV (SCID-1). Exclusion criteria for patients were being younger than 18 and older than 65 years old, being illiterate, having a comorbid mental retardation and/or active substance or alcohol dependence, and/or having the first episode of schizophrenia. The control group was also interviewed by using the semistructured clinical interview for DSM-IV (SCID-1), for both current and previous psychiatric diagnosis. Exclusion criteria for the control group were being younger than 18 and older than 65 years old, being illiterate, having a current psychiatric disorder, and having a first-degree relative diagnosed with schizophrenia.

Study design

This study was conducted in two steps. At first step, patients with schizophrenia with acute psychotic symptoms (Brief Psychiatric Rating Scale [BPRS]>30 points) were given the BPRS (Overall and Gorham, 1962), the Scale for Assessment of Positive Symptoms (SAPS) (Andreasen, 1990), the Scale for Assessment of Negative Symptoms (SANS) (Andreasen, 1990), the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1992), as well as a sociodemographic information form (which also includes a medical and family history) designed by the authors for this study. Then, the patients were evaluated by BPRS weekly, and as soon as their BPRS score decreased below 30 points, they were included to the second step. At second step of the study, patients were given the Childhood Trauma Questionnaire (CTQ) (Bernstein et al., 1994) and the Social Readjustment Rating Scale (SRRS) (Holmes and Rahe, 1967), and blood samples were collected for genetic analysis. Since both CTQ and SRRS are self-report scales, and having severe psychotic symptoms may affect self-report, we preferred to wait until patients' BPRS scores were below 30, to increase the reliability of their answers.

The control group was only evaluated once. During this evaluation, a semistructured psychiatric interview was made to exclude the ones with the current psychiatric disorder. Their family history for psychotic disorders was also taken. Those who were included in the study were given CTQ and SRRS, and their blood samples were collected for genetic analysis.

Genotyping analysis

Genomic DNA was collected from peripheral blood samples using the Heliosis Kit (Metis Biotechnology, Ankara, Turkey), following the manufacturer's instructions. The DISC1 polymorphisms (−274G>C, Ser704Cys and Gln264Arg) were genotyped by the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methods. The Mastercycler gradient (Eppendorf, Hamburg, Germany) thermal cycler was used for amplifications.

The gene-specific primer sequences, PCR products, and restriction endonucleases are shown in Table 1.

Table 1.

The Gene-Specific Primer Sequences, Polymerase Chain Reaction Products, and Restriction Endonucleases

Polymorphisms	Primers	PCR products (bp)	REs	Alleles (bp)	References
−274G>C (rs3738398)	F: 5′-CTCACATCCCTCCATCTTCT-3′	291	MspI	C allele: 291
	R: 5′-CGAGTCCGCTGTTTCCTTT-3′			G allele: 163, 128
Ser704Cys (rs821616)	F: 5′-GTATTGGGCTGCTGAGTCTG-3′	540	BsrI	A allele: (Ser): 540	Qu et al. (2007)
	R: 5′-GACCTCTTTCTGTTCACCTCC-3′			T allele: (Cys): 336,204
Gln264Arg (rs3738401)	F: 5′-GGTCCCCCCAACCCCTCC-3′	386	DdeI	G allele: 123+263 (Arg)	Zhang et al. (2006)
	R: 5′-CATCCCCGGAGCCGCTGC-3′			A allele: 123+84+179 (Gln)

REs, restriction endonucleases.

The DISC1 gene −274G>C (rs3738398) was amplified in a final volume of 50 μL, containing 3 μL genomic DNA, 1.5 mM MgCl₂, 0.2 mM dNTP, 50 pmol/mL of each primer, and 1.0 U/mL Taq DNA polymerase. Thermal cycling conditions were settled as 94°C for 30 s, 62°C for 60 s for 30 cycles, and then 72°C for 1 min. After the incubation time, the fragments were separated on a 2% agarose gel that was stained with ethidium bromide and visualized by the Gel Logic 100 image system (Kodak, Rochester, NY). This PCR reaction produces a fragment of 291-bp long that was digested with MspI restriction endonuclease (MBI Fermentas, Vilnius, Lithuania) at 37°C for 16 h. The restriction fragments were 291 bp for the C allele, and 163 and 128 bp for the G allele.

For Ser704Cys (rs821616), thermal cycling was based on Qu et al.'s (2007) PCR conditions. This PCR reaction produces a fragment of 540-bp long that was digested with BsrI restriction endonuclease (MBI Fermentas) at 37°C for 16 h. After the incubation time, the fragments were separated on a 2% agarose gel that was stained with ethidium bromide and visualized by the Gel Logic 100 image system (Kodak). The electrophoresed AA genotype is represented by the band of 540 bp, whereas the TT genotype gives two bands, 336 and 204 bp.

For Gln264Arg (rs3738401), thermal cycling was based on Zhang et al.'s (2006). The experiment was carried out of digesting the PCR products with DdeI restriction endonuclease (Roche Diagnostics) at 37°C for 16 h followed by electrophoresis in a 2% agarose gel, containing 0.5% ethidium bromide. The restriction fragments were 123 and 263 bp for the G allele, and 123, 84, and 179 bp for the A allele.

Statistical analysis

All data were analyzed by using the SPSS 10.0 package program. Mann–Whitney U test was used for comparison of patients' and controls' scores from scales. The correlation between SANS, SAPS, BPRS, and CDSS scores of both groups was evaluated by Pearson correlation analysis. Risk factors were found using a multivariate linear regression analysis. A P score below 0.05 was considered as statistically significant. For statistical analysis related to the DISC1 gene, the Hardy–Weinberg, Pearson's chi-square and for haplotype analysis, EM algorithm-based Arlequin version 3.1 and HAP (Haplotype Resolution version 3.0) software were used.

Results

Sociodemographical information

About 53% of the patients were men, and 59% were single, while 39% of controls were women (p=0.047), and 54% were single (p=0.011). The mean age of patients (36.48±11.27) were significantly (p=0.018) higher than controls (32.45±11.82). About 62% of patients and 89% of controls had at least 8 years of education (p<0.001). The majority of the patients did not have a job (71%), whereas the majority of controls were working (80%, p<0.001).

About 30% of the patients had a first- or second-degree relative with a psychiatric diagnosis, while only 6% of controls had a family history of psychiatric disorder (p<0.001). About 15% of the patients had only one relative with schizophrenia, and 15% had more than one schizophrenic relative.

Clinical and treatment information of patients

About 60% of the patients were using antipsychotic monotherapy, while the remaining patients were on two antipsychotic combination treatments. Mean dosage of antipsychotics equivalent to chlorpromazine dosage was 828.91±474.66 mg/day. The mean illness duration was 10.47±9.10 years.

Mean scores of patients from clinical evaluation scales were as follows: 51.73±29.31 from SANS, 52.44±38.26 from SAPS, 8.29±5.10 from CDSS, 46.32±18.03 from BPRS before treatment (BPRS-1), and 23.332±13.47 from BPRS after treatment (BPRS-2).

Comparison of patients' and controls' scores

A comparison of patients' and controls' mean scores from SRSS and CTQ is shown in Table 2. According to this comparison, the total mean score of patients' from CTQ was significantly higher than controls (90.01±19.92 and 72.25±17.49 respectively, p=0<0.001), and this difference was caused by the scores from Emotional Neglect, Emotional Abuse, Physical Neglect, and Physical Abuse subunits. There was no statistically significant difference between patients' and controls' mean scores from SRRS (p>0.05).

Table 2.

Comparison of Patients' and Controls' Mean Scores from the Childhood Trauma Questionnaire and the Social Readjustment Rating Scale

	Patients Mean (SD)	Controls Mean (SD)	P
CTQ-total	90.01 (19.92)	72.25 (17.49)	<0.001
Emotional neglect	40.44 (10.32)	29.47 (11.15)	<0.001
Emotional abuse	16.95 (6.02)	14.61 (5.26)	<0.001
Physical neglect	11.57 (3.10)	9.47 (1.98)	<0.001
Physical abuse	13.24 (5.03)	11.64 (2.65)	0.018
Sexual abuse	7.38 (1.65)	7.25 (0.89)	0.394
SRRS	261.96 (278.01)	229.64 (264.14)	0.388

CTQ, Childhood Trauma Questionnaire; SRRS, Social Readjustment Rating Scale.

Genetic analysis

The genotype frequencies of the −274G>C and Gln264Arg variations were in the Hardy–Weinberg equilibrium (p>0.05). Nonetheless, for the Ser704Cys, the distribution of genotypes in the control group (p>0.05) did not differ significantly from expected values, but there was a significant deviation from the Hardy–Weinberg equilibrium in the case group (p<0.05). The distribution of allelic and genotypic frequencies of all three single-nucleotide polymorphisms (SNPs) of the DISC1 gene in patients and controls are presented in Table 3. The selected SNPs of the DISC1 gene did not demonstrate an association with the likelihood of acute symptoms of patients with schizophrenia in our study (p>0.05). The frequencies of DISC1 haplotypes along with the estimations of odds ratios in both patients and controls are presented in Table 4. There were no significant differences between patients and controls with regard to the −274G>C, c.791G>A, and c.2110A>T haplotypes (p>0.05).

Table 3.

Comparison of Patients' and Controls' −274G>C, c.791G>A, and c.2110A>T Polymorphisms of the DISC1 Gene

Polymorphism	Patients (n=100)	Controls (n=97)	p-Value	OR (95% CI)	p-Value
−274G>C (rs3738398)
CC	23 (%23)	25 (%25.8)	0.893	1.00^a
GC	49 (%49)	45 (%46.4)		1.18 (0.59–2.37)	0.635
GG	28 (%28)	27 (%27.8)		1.12 (0.52–2.45)	0.762
GC+GG^b	77 (%77)	72 (%74.2)		1.16 (0.60–2.23)	0.650
Alleles
C	95 (%47.5)	95 (%49)		1.00^a
G	105 (%52.5)	99 (%51)		1.06 (0.71–1.58)	0.770
c.791G>A (Arg264Gln, rs3738401)
GG (Arg/Arg)	52 (%52)	42 (%43.3)	0.330	1.00^a
AG (Arg/Gln)	40 (%40)	49 (%50.5)		0.66 (0.37–1.18)	0.161
AA (Gln/Gln)	8 (%8)	6 (%6.2)		1.08 (0.35–3.35)	0.898
AG+AA^c	48 (%48)	55 (%56.7)		0.71 (0.40–1.24)	0.222
Alleles
G	144 (%72)	133 (%68.6)		1.00^a
A	56 (%28)	61 (%31.4)		0.85 (0.55–1.31)	0.455
c.2110A>T (Ser704Cys, rs821616)
AA (Ser/Ser)	49 (%49)	45 (%46.4)	0.145	1.00^a
AT (Ser/Cys)	50 (%50)	46 (%47.4)		1.00 (0.56–1.76)	0.995
TT (Cys/Cys)	1 (%1)	6 (%6.2)		0.15 (0.02–1.32)	0.059
AT+TT^d	51 (%51)	52 (%53.6)		0.90 (0.51–1.58)	0.714
Alleles
A	148	136		1.00^a
T	52	58		0.82 (0.53–1.28)	0.389

Reference genotype/allele.

Comparison of individuals with CC genotype and GC+GG genotype.

Comparison of individuals with GG genotype and AG+AA genotype.

Comparison of individuals with AA genotype and AT+TT genotype.

DISC1, Disrupted in Schizophrenia-1; CI, confidence interval; OR, odds ratio.

Table 4.

The DISC1 Polymorphisms (−274G>C, c.791G>A, and c.2110A>T) Haplotypes Comparison in the Patients and Control Groups

Haplotypes	Patients (2n=200) (%)	Controls (2n=194) (%)	OR (95% CI)	p-Value
CGA	69 (34.5%)	60 (30.9%)	1^a
GAA	37 (18.7%)	42 (21.8%)	0.77 (0.44–1.34)	0.352
GGA	42 (20.8%)	32 (16.4%)	1.14 (0.64–2.03)	0.653
CGT	22 (11.1%)	30 (15.5%)	0.64 (0.33–1.22)	0.173
GAT	15 (7.4%)	14 (7.0%)	0.93 (0.42–2.09)	0.863
GGT	11 (5.6%)	11 (5.8%)	0.87 (0.35–2.15)	0.762
CAT	4 (1.9%)	3 (1.6%)	1.16 (0.25–5.39)	1.0
CAA	—	2 (1.0%)	NC	NC

Reference haplotype.

NC, not calculated.

Variables that affect clinical presentation of schizophrenia

The effect of the DISC1 gene −274G>C, c.791G>A, and c.2110A>T polymorphisms on patients' mean scores of clinical assessment scales was determined by the Kruskal–Wallis and Mann–Whitney U analyses. According to these analyses, none of the different genotypes of these polymorphisms had a statistically significant effect on patients' mean scores from SANS, SAPS, CDSS, BPRS-1, and BPRS-2 (p>0.05).

The effects of CTQ and SRRS scores on SANS, SAPS, CDSS, BPRS-1, and BPRS-2 were found by the Pearson correlation analysis. According to this analysis, Emotional Abuse subunit of CTQ is negatively and significantly correlated with SANS (r=−0.229, p=0.023). In addition, the mean score of SRSS is negatively and significantly correlated with SAPS (r=−0.238, p=0.019), SANS (r=−0.285, p=0.005), and BPRS-1 (r=−0.292, p=0.032).

The effects of possible variables on BPRS-1, BPRS-2, SANS, SAPS, and CDSS scores were found by a multivariate linear regression analysis, and the results are shown in Table 5. According to this analysis, having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=−67.547, −21.473; p<0.01), and BPRS-1 scores (95% CI=−51.405, −6.885; p=0.01), while emotional abuse at childhood significantly affected SANS scores (95% CI=−37.300, −10.401; p<0.01).

Table 5.

Multivariate Linear Regression Analysis for Possible Risk Factors on SAPS, SANS, CDSS, BPRS-1, and BPRS-2

	OR (P)
	SAPS	SANS	CDSS	BPRS-1	BPRS-2
Childhood trauma (−/+)	0.04 (0.70)	0.12 (0.28)	0.04 (0.77)	−0.02 (0.89)	−0.06 (0.65)
Emotional abuse (−/+)	0.03 (0.74)	−0.40 (0.00)^b	−0.00 (0.97)	0.19 (0.25)	0.09 (0.51)
Stressful life event (−/+)	−0.39 (0.00)^b	−0.19 (0.05)	−0.10 (0.50)	−0.37 (0.01)^b	−0.20 (0.09)
c.719G>A A allele (+/−)	−0.04 (0.79)	0.06 (0.72)	−0.06 (0.78)	0.06 (0.75)	0.11 (0.42)
−274G>C G allele (+/−)	−0.04 (0.73)	−0.05 (0.66)	0.09 (0.62)	−0.08 (0.66)	−0.21 (0.36)
Risky genotype (−/+)^a	0.04 (0.81)	0.00 (0.96)	0.13 (0.63)	−0.15 (0.56)	0.06 (0.76)

−=AA or AG genotype of c.719 G>A polymorphism/GG or GC genotype of −274G>C polymorphism/AA or AT genotype of c.2110 A>T polymorphism; +=GG genotype of c.719 G>A polymorphism/CC genotype of −274G>C polymorphism/TT genotype of c.2110 A>T polymorphism.

Statistically significant for p<0.05.

SAPS, Scale for Assessment of Positive Symptoms; SANS, Scale for Assessment of Negative Symptoms; CDSS, Calgary Depression Scale for Schizophrenia; BPRS, Brief Psychiatric Rating Scale.

Discussion

We believe that there are two important results of this study. First one is about the DISC1 gene; there was no statistically significant difference between patients and healthy controls with regard to three polymorphisms of the DISC1 gene, and different genotypes of DISC1 did not have a significant effect on clinical features of acute symptoms of schizophrenia. We also calculated the haplotype frequencies of the DISC1 polymorphisms for both groups, but again, we failed to find any significant differences between two groups. As said before, there are negative (Devon et al., 2002; Kockelkorn et al., 2004) as well as positive (Hennah et al., 2003; Hodgkinson et al., 2004; Callicott et al., 2005; Thomson et al., 2005; Palo et al., 2007; Qu et al., 2007; Kim et al., 2008; Saetre et al., 2008; Schumacher et al., 2009; Tomppo et al., 2009; Chakirova et al., 2011; Shaikh et al., 2011; Wei et al., 2012) studies about the association between the DISC1 gene and schizophrenia. In a very recent meta-analysis, it was concluded that there was no evidence that common variants at the DISC1 locus are associated with schizophrenia (Mathieson et al., 2012). Efforts have also been carried out to find out if SNPs of the DISC1 gene have an association with treatment resistance in schizophrenia, but results have also been inconclusive; one study had positive (Mouaffak et al., 2011), yet another had negative, results (Hotta et al., 2011).

These inconclusive findings about the association between the DISC1 gene and schizophrenia may result from the fact that the gene is very large and has many different SNPs, and studies have come from many different populations. The DISC1 gene SNPs that were significantly associated with schizophrenia are as follows: rs1538979 and rs 821633 in an European sample (Schumacher et al., 2009); rs 1120303, rs7412571, and rs 17806986 in a Finnish sample (Tomppo et al., 2009); and rs 3737597 in a Scandinavian sample (Saetre et al., 2008). One of the SNPs that we investigated in our study, namely, rs821616, has found to be significantly associated with schizophrenia in Korean (Kim et al., 2008), Chinese (Qu et al., 2007) and American (Callicott et al., 2005) samples. Besides, this SNP showed a significant association with P300 latency, which is considered as an endophenotype for psychosis (Shaikh et al., 2011), and caused a significant defect on verbal fluency of patients with schizophrenia and bipolar (Palo et al., 2007). To our knowledge, this study is the only one that has investigated the association between the DISC1 gene and schizophrenia in a Turkish sample, and there are no previous studies to date that investigate the effect of different polymorphisms of the DISC1 gene on clinical features of schizophrenia. For this sample, there was no effect of different polymorphisms of the DISC1 gene on positive, negative, or depressive symptom formation during the acute phase of schizophrenia. One of the reasons for our failure to find a significant association between these 3 SNPs on the DISC1 gene and schizophrenia may be that the patient and control groups were not matched according to their genders. Previous studies have found that contribution of the DISC1 gene polymorphisms to schizophrenia development may be gender-dependent (Hennah et al., 2003; Schumacher et al., 2009).

Second important result of this study is that both environmental factors we included in this study, namely, childhood traumatic events and stressful life events, had significant effects on different symptom clusters of the acute phase of schizophrenia, and these effects were independent of different genotypes of the DISC1 gene. Patients reported significantly higher amounts of emotional abuse and neglect, as well as physical abuse and neglect, during their childhood than healthy controls, yet one should always keep in mind the possible recall bias for CTQ. There is emerging evidence that childhood traumatic events are related to more severe symptoms among people with schizophrenia and other severe mental illnesses (Muenzenmaier et al., 1994; Ross et al., 1994; Ellason and Ross, 1997). In a national cohort study from Sweden, social adversity in childhood was found to be independently associated with the risk of developing schizophrenia and other psychosis later in life (Castine et al., 1998). In addition, emotional abuse in childhood was significantly associated with less negative symptoms during the acute phase of schizophrenia in our sample. This result needs further support from other studies, since none of the studies investigating the effect of childhood adverse events on future symptom formation of schizophrenia have focused on negative symptoms.

In our sample, recent stressful life events were significantly, yet negatively, correlated with positive, negative, and overall psychotic symptoms, but not with depressive symptoms during the acute phase of schizophrenia. The association between stressful life events and onset and relapse of schizophrenia has been shown previously (Day et al., 1987; Ventura et al., 1989; Malla et al., 1990; Hirsch et al., 1996). Rather than simply peaking in the few weeks before a relapse and acting merely as a trigger, it has been reported that an increased rate of life events occur over a more lengthy period before the onset of psychosis (McDonald and Murray, 2000). The SRRS scale, which we used for evaluating the recent life events in our sample, asks for the event that occurred during the previous year. There are data that suggest that recent life events are a more frequent contributing factor to the acute psychiatric admission of those subjects experiencing their first three episodes of schizophrenia compared to those subjects experiencing episodes beyond their third (Wicks et al., 2005). This finding was found to be consistent with the affective disorders literature (e.g., kindling model), and supports the notion that initial episodes of psychiatric illness appear to be associated with recent life events, while recurrent episodes are more likely to occur spontaneously (Post, 1992). Unfortunately, we did not record the number of previous episodes of schizophrenia in our sample, but since the overall mean duration of illness was ∼10 years, we can assume that patients in our sample had a number of previous episodes.

There are some limitations of our study. Our sample was rather small for a genetic study, and patients come from only one center, so our results cannot be generalized to whole schizophrenia population. Besides, some of our scales were self-reported (scales for adverse childhood events and stressful recent life events), yet these scales were filled by our patients after the acute symptoms of schizophrenia calmed down. In addition, DISC1 is a very large gene with many SNPs, and this study evaluated only three SNPs. Despite these limitations, we believe that our study is of importance, since, to our knowledge, this is the first study that investigates effects of both genetic and environmental factors on acute symptoms of schizophrenia. It is possible that different SNPs in the DISC1 gene do not show an epigenetic change, and this fact may be the reason for inconclusive results among different studies. We think that new methods that may show the epigenetic changes caused by environmental factors are needed to better understand the effects of genes on schizophrenia development.

Footnotes

Disclosure Statement

This work is supported by a grant (01/2009-33) from the Scientific Research Project Department of the Gazi University.

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