|Year : 2015 | Volume
| Issue : 3 | Page : 118-123
Catechol-O-methyltransferase gene polymorphisms in Saudi cases with schizophrenia
Ashraf Tantawy MD 1, Abduhamid Al-Yahia2, Yasser Raya3, Abdurrahman Al-Mohaimeed4, Ahmad Settin5
1 Department of Psychiatry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Psychiatry, Buraidah Mental Hospital, Al-Qassim, Kingdom of Saudi Arabia
2 Department of Psychiatry, College of Medicine, Qassim University, Al-Qassim, Saudi Arabia
3 Department of Psychiatry, College of Medicine, Qassim University, Al-Qassim, Kingdom of Saudi Arabia; Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4 Department of Family and Community Medicine, College of Medicine, Qassim University, Al-Qassim, Saudi Arabia
5 Department of Paediatrics, College of Medicine, Qassim University, Al-Qassim, Saudi Arabia
|Date of Submission||12-Jan-2015|
|Date of Acceptance||17-Mar-2015|
|Date of Web Publication||30-Sep-2015|
Department of Psychiatry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Psychiatry, Buraidah Mental Hospital, Al-Qassim, Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
This work was conducted to test for the association of genetic polymorphisms of catechol-O-methyltransferase (COMT) with the susceptibility and clinical patterns of schizophrenia among Saudi patients.
Participants and methods
This is a case-control study involving 79 patients fulfilling the ICD-10 criteria of schizophrenia and 82 healthy controls. Patients were interviewed by different tools, which included the Diagnostic Interview for Genetic Studies (DIGS/V4.0), the Positive and Negative Symptoms Scale (PANSS), and the World Health Organization Disability Assessment Schedule (version 2.0) (WHO/DAS II). All patients and controls were screened for COMT G >A gene polymorphisms using the real-time PCR technique.
Frequencies of all genetic variants of COMT G >A [V158M] did not show a significant difference on comparing cases with controls (P > 0.05). Comparing the frequencies of genetic variants in cases having positive parental consanguinity and a family history of schizophrenia or other mental illnesses with those without a history also showed nonsignificant results (P > 0.05). A stratified analysis related to severity scores and associated clinical illnesses also showed a nonsignificant difference (P > 0.05).
Polymorphism related to COMT G >A was not associated with the susceptibility and the severity of schizophrenia among Saudi cases.
Keywords: catechol-O-methyltransferase, gene polymorphism, Saudi Arabia, schizophrenia
|How to cite this article:|
Tantawy A, Al-Yahia A, Raya Y, Al-Mohaimeed A, Settin A. Catechol-O-methyltransferase gene polymorphisms in Saudi cases with schizophrenia. Egypt J Psychiatr 2015;36:118-23
|How to cite this URL:|
Tantawy A, Al-Yahia A, Raya Y, Al-Mohaimeed A, Settin A. Catechol-O-methyltransferase gene polymorphisms in Saudi cases with schizophrenia. Egypt J Psychiatr [serial online] 2015 [cited 2017 Jun 23];36:118-23. Available from: http://new.ejpsy.eg.net/text.asp?2015/36/3/118/166348
| Introduction|| |
Schizophrenia is a psychiatric disorder that affects ~1% of the world population, usually begins before 25 years of age and persists throughout life, and affects persons of all social classes (McGuffin et al., 1995; APA, 2000). Schizophrenia, like most psychiatric disorders, is a complex disorder that cannot be explained by a single genetic or environmental factor (McGuffin et al., 1995). The heritability of schizophrenia is estimated to be around 80%, with around a 10-fold risk increase in first-degree relatives (Owen et al., 2005). Association studies, mainly with candidate genes, have also not provided consistent results (Pulver, 2000; Shifman et al., 2002; Glatt et al., 2003; Wonodi et al., 2003).
Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamines, including dopamine (Axelrod and Tomchick, 1958; Grossman et al., 1992; Slifstein et al., 2008).Two codominant alleles (G and A) in exon 4 of the COMT gene influence the amino acid structure (Val or Met) at codon 158. The COMT enzyme activity is genetically polymorphic, with a trimodal distribution (high activity in the Val/Val genotype, intermediate activity in the Val/Met genotype, and low activity in the Met/Met genotype) (Grossman et al., 1992). Results of the studies on the Val158Met polymorphism of the COMT gene are conflicting (Lachman et al., 1996; Shifman et al., 2002; Glatt et al., 2003; Wonodi et al., 2003; Chen et al., 2004a, 2004b), with a number of studies suggesting a possible effect of the Val158Met polymorphism on the vulnerability to schizophrenia (Kunugi et al., 1997; Ohmori et al., 1998; Egan et al., 2001; Liou et al., 2001; Weinberger et al., 2001; Shifman et al., 2002; Kremer et al., 2003; Wonodi et al., 2003; Bertolino et al., 2004; Chen et al., 2004a, 2004b; Sazci et al., 2004; Meyer-Lindenberg et al., 2006; Nunokawa et al., 2007; Park et al., 2009; Hoenicka et al., 2010; Costas et al., 2011), and others showing no association or are not specific to schizophrenia (Daniels et al., 1996; Strous et al., 1997; Karayiorgou et al., 1998; Chen et al., 1999; Norton et al., 2002; Glatt et al., 2003; Inada et al., 2003; Mattay et al., 2003; Palmatier et al., 2004; Fan et al., 2005; Galderisi et al., 2005; Munafo et al., 2005; Williams et al., 2005; Barnett et al., 2007; Gur et al., 2007; Kim et al., 2008; Okochi et al., 2009; Park et al., 2009; Nieratschker et al., 2010; Lajin et al., 2011). Although the effect of the COMT gene on the deficit (negative symptoms)/nondeficit (positive symptoms) subtype of schizophrenia has failed to be shown (Fan et al., 2005; Williams et al., 2005; Wonodi et al., 2006; Fanous and Kendler, 2008), some studies found an association between the COMT gene and the severity of positive symptoms: aggressive or violent behavior in schizophrenic individuals (Roffman et al., 2006; Hill et al., 2011). Several aspects of COMT function, including its transcription and its inactivation of dopamine by transmethylation, depend on the availability of one-carbon moieties, which in turn is strongly influenced by the activity of methylenetetrahydrofolate reductase (MTHFR) (Sasaki et al., 2003). Therefore, it was suggested that the MTHFR 677C >T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val >Met (Kang et al., 2010).
This work was conducted to check for the association of polymorphic variants of COMT A >G [Val158Met] with the susceptibility and the clinical pattern of schizophrenia among Saudi individuals.
| Participants and methods|| |
This was a randomized case-control study involving 79 patients with schizophrenia and 82 healthy unrelated controls. Cases were selected randomly from the mental health hospital in Al-Qassim region, Saudi Arabia. They included 57 (72.2%) male and 22 (27.8%) female patients. Their mean ± SD age of onset of the disease was 24.3±7.6 years. Diagnostic tools were based on a semistructured psychiatric interview involving the Diagnostic Interview for Genetic Studies Version 4.0 (DIGS/V4.0) (Bierut et al., 2005) in addition to the International Classification of Mental and Behavioral Disorders (ICD-10) (WHO, 1994). Exclusion criteria included cases with mental retardation, chronic debilitating illness, organic brain disease, substance abuse disorder, or psychiatric comorbidities. Controls were selected from blood donors who were absolutely free of and had a negative family history of any psychiatric illness. They included 49 (56.1%) male and 36 (43.9%) female individuals with a mean age ± SD of 27.2 ± 11.1 years. An ethical approval was taken from all participants before the start of the study, and approval from the Research and Ethical committees of Al-Qassim University, Saudi Arabia, was obtained.
Measurement of disability and the severity
The severity of schizophrenia was assessed by the application of the commonly used rating scale: the Positive and Negative Symptoms Scale (PANSS) for schizophrenia. To assess a patient using PANSS, an ~45-min clinical interview is conducted. The patient is rated from 1 to 7 (1 =absent, 2 = minimal, 3 = mild, 4 = moderate, 5 = moderate severe, 6 = severe, and 7 = extreme) on 30 different symptoms on the basis of the interview as well as reports of family members or primary-care hospital workers (Annicchiarico, 2003). In contrast, disability was measured with the World Health Organization Disability Assessment Schedule (version 2.0) (WHO/DAS II). This interview measures the self-reported difficulty of functioning in six major domains that are considered important in most cultures: D1, understanding and communicating; D2, getting around; D3, self-care; D4, getting along with people; D5, life activities; and D6, participation in the society (Kay et al., 1987).
DNA extraction and real-time PCR
The isolation of DNA was performed on a MagNA Pure LC instrument (Roche Molecular Biochemicals, Mannheim, Germany). Real-time PCR was performed using the light cycler instrument (Roche Diagnostics, Mannheim, Germany). Oligonucleotide primers and fluorescence-labeled hybridization probes were designed for amplification and sequence-specific detection of COMT gene polymorphisms. Primers and probes were obtained from TIB MolBiol (Berlin, Germany). The master mixture contained 2 μl of a 10 mixture of LightCycler FastStart DNA master hybridization probes (Roche Diagnostics), 5 mmol/l MgCl 2 (final concentration), a 1 μmol/l final concentration of primers, and a 0.2 μmol/l final concentration of hybridization probes. Fluorescence curves were analyzed with the Light Cycler software (version 3.5.3). Each run contained the wild type, the mutant, and heterozygous standard control DNA in addition to a negative control (blank reagent and water). Each result was confirmed by the specific peak in the corresponding melting curve.
Data were processed and analyzed using the Statistical Package of Social Science (SPSS, version 13.0, SAS Institute, Cary, NC, USA). The frequency of the studied genotypic and allelic polymorphisms among cases was compared with that of controls and tested for a positive association using the χ2 -test, Fisher's exact test, and odds ratio with the 95% confidence interval considering a minimum level of significance of P value less than 0.05 (SPSS, 2002).
| Result|| |
The frequency of genetic variants related to COMT G >A [V158M] polymorphisms among schizophrenic patients compared with controls showed no statistically significant difference with regard to different models of inheritance such as the recessive (homozygosity of the rare allele vs. others), the codominant (homozygosity or heterozygosity of the rare allele vs. homozygosity of the wild-type allele), and the overdominant (heterozygosity vs. others) patterns [Table 1]. The Hardy-Weinberg equilibrium also showed no significant deviation of the observed frequencies from that of the expected frequencies, among both cases and controls, indicating a fairly selected population sample with no particular differences of cases and controls.
|Table 1 Gene polymorphic variants related to COMT G > A [V158M] among cases of schizophrenia compared with controls |
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Evaluation of the subtypes of schizophrenic patients revealed that among them, undifferentiated schizophrenia was the most common subtype (31, 39.24%), followed by the paranoid (25, 31.65%), the residual (18, 22.78%), and the hebephrenic (5, 6.33%) subtypes. Genetic predisposition of the disease was shown by the fact that 21 (26.58%) cases had a positive family history of schizophrenia, whereas 18 (22.78%) cases had a family history of other mental disorders, and only seven (8.86%) cases had positive parental consanguinity. Hypertension and diabetes were found among 12 (15.19%) and 16 (20.25%) cases, respectively. Comparing genetic variants in subgroups of cases regarding their sex, a positive family history of schizophrenia or other mental disorders, consanguinity, and any associated medical conditions such as diabetes, hypertension, and metabolic syndrome also showed a nonsignificant difference [Table 2] and [Table 3]. Evaluation of severity and disability scores through the calculation of their mean ± SD related to their individual genetic background showed a nonsignificant difference [Table 4].
|Table 2 Gene polymorphic variants related to COMT G >A [V158M] among cases of schizophrenia in relation to their demographic parameters |
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|Table 3 Gene polymorphic variants related to COMT G >A [V158M] among cases of schizophrenia in relation to their clinical parameters |
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|Table 4 Gene polymorphic variants related to COMT among schizophrenic patients in relation to severity of illness and disability scores |
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| Discussion|| |
This study was conducted to check for the association of genetic polymorphisms of the COMT gene with schizophrenia among affected cases in Saudi Arabia. Although a number of studies including a meta-analysis have suggested an association between schizophrenia and the COMT polymorphism in several populations (Kunugi et al., 1997; Ohmori et al., 1998; Egan et al., 2001; Liou et al., 2001; Weinberger et al., 2001; Shifman et al., 2002; Kremer et al., 2003; Wonodi et al., 2003; Bertolino et al., 2004; Chen et al., 2004a, 2004b; Sazci et al., 2004; Meyer-Lindenberg et al., 2006; Nunokawa et al., 2007; Allen et al., 2008; Park et al., 2009; Hoenicka et al., 2010; Costas et al., 2011), this study failed to demonstrate any significant association between these polymorphisms and the susceptibility to schizophrenia among Saudi individuals. Nonetheless, this negative association was also reported in other studies and meta-analyses among several other populations (Daniels et al., 1996; Strous et al., 1997; Karayiorgou et al., 1998; Chen et al., 1999; Norton et al., 2002; Glatt et al., 2003; Inada et al., 2003; Mattay et al., 2003; Palmatier et al., 2004; Fan et al., 2005; Galderisi et al., 2005; Munafo et al., 2005; Williams et al., 2005; Barnett et al., 2007; Gur et al., 2007; Kim et al., 2008; Okochi et al., 2009; Park et al., 2009; Kang et al., 2010; Nieratschker et al., 2010; Lajin et al., 2011). Such inconsistent and controversial results might be confirmatory of the complex nature of the disease, presumably having a polygenic or a multifactorial basis. It might also be explained by the ethnic diversity and differing environmental factors. Technical errors might also warrant further research work with more precise methodologies and larger population samples. Schizophrenia among the Saudi cases of this study had some issues pointing toward its genetic background, such as a positive family history of schizophrenia among more than one-fourth of the cases, a positive family history of mental disorders among more than one-fifth of them, and positive parental consanguinity in ~9% of them. However, these subgroups did not show an association with the genetic variants of the COMT gene. Also, these genetic variants were not associated with schizophrenia subtypes or with other clinical disorders such as diabetes and hypertension. These results are consistent with prior reports on the negative genetic association with the subtypes of schizophrenia (Fan et al., 2005; Williams et al., 2005; Fanous and Kendler, 2008; Hill et al., 2011), although some linkage and association studies have suggested that some susceptibility genes are etiologic factors for more or less specific subtypes of schizophrenia (Karayiorgou et al., 1998; Chen et al., 1999; Kirkpatrick et al., 2001). This study also showed a negative association for positive and negative disease manifestations. These results are inconsistent with some other studies that showed some association (Weinberger et al., 2001; Bilder et al., 2004; Levy and Dubois, 2006; Roffman et al., 2006; Wonodi et al., 2006; Fanous and Kendler, 2008; Gu et al., 2009; Pan et al., 2009; Hill et al., 2011; Ceaser et al., 2012) and also are in agreement with other studies that failed to show any association (Fan et al., 2005; Williams et al., 2005; Wonodi et al., 2006; Fanous and Kendler, 2008; Maher, 2008). It was previously proven through a meta-analysis and an association study that there is no direct relationship between COMT and suicidal behavior (Calati et al., 2011; Soyka, 2011). These finding are inconsistent with most of the previous studies (Green, 1996; Egan et al., 2001; Bertolino et al., 2004; Meyer-Lindenberg et al., 2006; Gur et al., 2007; Ceaser et al., 2012). The majority of the individuals with schizophrenia were treated with antipsychotic medication and most of these individuals were treated with atypical drugs. The medication status could have interacted with the influences of COMT genotypes in our study, but COMT effects have previously been observed in nontreated patients (Woodward et al., 2007). The difference can be explained by the relatively small sample size, which might have limited the detection of associations between the COMT gene and subtypes of schizophrenia. We conclude that polymorphisms related to COMT G >A were not associated with the susceptibility to schizophrenia among Saudi cases.
| Acknowledgements|| |
The authors are grateful to King Abdul Aziz City for Science and Technology for sponsoring this scientific work totally. The authors also appreciate and are grateful to the staff of the Ministry of Health, Buraydah Mental Health Hospital, Al-Qassim, KSA, for their help and cooperation.
Conflict of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]