|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 Aug 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.
| References|| |
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, et al
. (2008). Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40:827-834.
Annicchiarico R (2003). New methodology for disability assessment: analysis of WHO-Disability Assessment Schedule II with clustering based on rules. AI Communications 16:213-215.
American Psychiatric Association (APA) (2004). Practice guideline for the treatment of patients with schizophrenia
, Second Edition. Am J Psychiatry 161 (Suppl. 2), 1-56.
Axelrod J, Tomchick R (1958). Enzymatic O
-methylation of epinephrine and other catechols. J Biol Chem 233:702-705.
Barnett JH, Jones PB, Robbins TW, Muller U (2007). Effects of the catechol-O
-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 12:502-509.
Bertolino A, Caforio G, Blasi G, De Candia M, Latorre V, Petruzzella V, et al.
(2004). Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 161:1798-1805.
Bierut LJ, Coryell W, Drain CE, Gershon E, Kassen L, Kelsoe J, et al.
(2005). Diagnostic Interview for Genetic Studies Version 4.0/BP (DIGS/V4.0)
. Rockville, Maryland: National Institutes of Mental Health.
Bilder RM, Volavka J, Lachman HM, Grace AA (2004). The catechol-O
-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29:1943-1961.
Calati R, Porcelli S, Giegling I, Hartmann AM, Möller HJ, De Ronchi D, et al.
-methyltransferase gene modulation on suicidal behavior and personality traits: review, meta-analysis and association study. J Psychiatr Res 45:309-321.
Ceaser A, Csernansky JG, Barch DM (2013). COMT influences on prefrontal and striatal blood oxygenation level-dependent responses during working memory among individuals with schizophrenia, their siblings, and healthy controls, Cogn Neuropsychiatry 18:257-283.
Chen CH, Lee YR, Chung MY, Wei FC, Koong FJ, Shaw CK, et al
. (1999). Systematic mutation analysis of the catechol O
-methyltransferase gene as a candidate gene for schizophrenia. Am J Psychiatry 156:1273-1275.
Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, et al.
(2004). Functional analysis of genetic variation in catechol-O
-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807-821.
Chen X, Wang X, O'Neill AF, Walsh D, Kendler KS (2004). Variants in the catechol-O
-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry 9:962-967.
Costas J, Sanjuán J, Ramos-Rios R, Paz E, Agra S, Ivorra JL, et al
. (2011). Heterozygosity at catechol-O
-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J Psychiatr Res 45:7-14.
Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC, et al
. (1996). No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O
-methyltransferase activity. Am J Psychiatry 153:268-270.
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al.
(2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98:6917-6922.
Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, et al
. (2005). Catechol-O
-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 57:139-144.
Fanous AH, Kendler KS (2008). Genetics of clinical features and subtypes of schizophrenia: a review of the recent literature. Curr Psychiatry Rep 10:164-170.
Galderisi S, Maj M, Kirkpatrick B, Piccardi P, Mucci A, Invernizzi G, et al.
(2005). COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. Schizophr Res 73:27-30.
Glatt SJ, Faraone SV, Tsuang MT (2003). Association between a functional catechol-O
-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case - control and family-based studies. Am J Psychiatry 160:469-476.
Green MF (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321-330.
Grossman MH, Emanuel BS, Budarf ML (1992). Chromosomal mapping of the human catechol-O
-methyltransferase gene to 22q11.1-q11.2. Genomics 12:822-825.
Gu Y, Yun L, Tian Y, Hu Z (2009). Association between COMT gene and Chinese male schizophrenic patients with violent behavior. Med Sci Monit 15:CR484-CR489.
Gur RE, Calkins ME, Gur RC, Horan WP, Nuechterlein KH, Seidman LJ, Stone WS (2007). The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophr Bull 33:49-68.
Hill LD, York TP, Kusanovic JP, Gomez R, Eaves LJ, Romero R, Strauss JF III (2011). Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia. PLoS One 6:e16681.
Hoenicka J, Garrido E, Martínez I, Ponce G, Aragüès M, Rodríguez-Jimnez R, et al
. PARGPARG (2010). Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet 153B:79-85.
Inada T, Nakamura A, Iijima Y (2003). Relationship between catechol-O
-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120:35-39.
Kang HJ, Choe BM, Kim SH, Son SR, Lee KM, Kim BG, Hong YS (2010). No association between functional polymorphisms in COMT and MTHFR and schizophrenia risk in Korean population. Epidemiol Health 32:e2010011
Karayiorgou M, Gogos JA, Galke BL, Wolyniec PS, Nestadt G, Antonarakis SE, et al
. (1998). Identification of sequence variants and analysis of the role of the catechol-O
-methyl-transferase gene in schizophrenia susceptibility. Biol Psychiatry 43:425-431.
Kay SR, Fiszben A, Opler LA (1987). The positive and negative symptoms scale (PANSS) for schizophrenia. Schizophr Bull 13:261-276.
Kim YR, Kim JH, Kim SJ, Lee D, Min SK (2008). Catechol-O
-methyltransferase Val158Met polymorphism in relation to aggressive schizophrenia in a Korean population. Eur Neuropsychopharmacol 18:820-825.
Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr (2001). A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 58:165-171.
Kremer I, Pinto M, Murad I, Muhaheed M, Bannoura I, Muller DJ, et al.
(2003). Family-based and case-control study of catechol-O
-methyltransferase in schizophrenia among Palestinian Arabs. Am J Med Genet B Neuropsychiatr Genet 119B:35-39.
Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, et al
. (1997). Catechol-O
-methyltransferase polymorphisms and schizophrenia: a transmission is equilibrium study in multiply affected families. Psychiatr Genet 7:97-101.
Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996). Human catechol-O
-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243-250.
Lajin B, Alachkar A, Hamzeh AR, Michati R, Alhaj H (2011). No association between Val158Met of the COMT gene and susceptibility to schizophrenia in the Syrian population. N Am J Med Sci 3:176-178.
Levy R, Dubois B. (2006). Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 16:916-928.
Liou YJ, Tsai SJ, Hong CJ, Wang YC, Lai IC (2001). Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. Neuropsychobiology 43:11-14.
Maher B (2008). Personal genomes: the case of the missing heritability. Nature 456:18-21.
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al.
(2003). Catechol O
-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100:6186-6191.
McGuffin P, Owen MJ, Farmer AE. (1995). Genetic basis of schizophrenia. Lancet 346:678-682.
Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, et al.
(2006). Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11:867-877.
Munafo MR, Bowes L, Clark TG, Flint J (2005). Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry 10:765-770.
Nieratschker V, Frank J, Mühleisen TW, Strohmaier J, Wendland JR, Schumacher J, et al
. (2010). The catechol-O
-methyl transferase (COMT) gene and its potential association with schizophrenia: findings from a large German case - control and family-based sample. Schizophr Res 122:24-30.
Norton N, Kirov G, Zammit S, Jones G, Jones S, Owen R, et al.
(2002). Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am J Med Genet 114:491-496.
Nunokawa A, Watanabe Y, Muratake T, Kaneko N, Koizumi M, Someya T (2007). No associations exist between five functional polymorphisms in the catechol-O
-methyltransferase gene and schizophrenia in a Japanese population. Neurosci Res 58:291-296.
Ohmori O, Shinkai T, Kojima H, Terao T, Suzuki T, Mita T, Abe K (1998). Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 243:109-112.
Okochi T, Ikeda M, Kishi T, Kawashima K, Kinoshita Y, Kitajima T, et al
. (2009). Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. Schizophr Res 110:140-148.
Owen MJ, O'Donovan MC, Harrison PJ (2005). Schizophrenia: a genetic disorder of the synapse? BMJ 330:158-159.
Palmatier MA, Pakstis AJ, Speed W, Paschou P, Goldman D, Odunsi A, et al.
(2004). COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol Psychiatry 9:859-870.
Pan CC, McQuoid DR, Taylor WD, Payne ME, Ashley-Koch A, Steffens DC (2009). Association analysis of the COMT/MTHFR genes and geriatric depression: an MRI study of the putamen. Int J Geriatr Psychiatry 24:847-855.
Park BL, Shin HD, Cheong HS, Park CS, Sohn JW, Kim BJ, et al.
(2009). Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality. J Hum Genet 54:709-712.
Pulver AE (2000). Search for schizophrenia susceptibility genes. Biol Psychiatry 47:221-230.
Roffman JL, Weiss AP, Goff DC, Rauch SL, Weinberger DR (2006). Neuroimaging-genetic paradigms: a new approach to investigate the pathophysiology and treatment of cognitive deficits in schizophrenia. Harv Rev Psychiatry 14:78-91.
Sasaki M, Kaneuchi M, Sakuragi N, Dahiya R (2003). Multiple promoters of catechol-O
-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer. Cancer Res 63:3101-3106.
Sazci A, Ergul E, Kucukali I, Kilic G, Kaya G, Kara I (2004). Catechol-O
-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. Brain Res Mol Brain Res 132:51-56.
Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, et al
. (2002). A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71:1296-1302.
Slifstein M, Kolachana B, Simpson EH, Tabares B, Cheng B, Duvall M, et al.
(2008). COMT genotype predicts cortical-limbic D1 receptor availability measured with [(11)C]NNC112 and PET. Mol Psychiatry 13:821-827.
Soyka M (2011). Neurobiology of aggression and violence in schizophrenia. Schizophr Bull 37:913-920.
SPSS (2002). Statistical package for social studies version 13.0
. Cary, NC, USA: SAS Institute.
Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM (1997). Analysis of a functional catechol-O
-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res 69:71-77.
Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, et al.
(2001). Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825-844.
WHO (1994). ICD-10 classification of mental and behavioural disorders - clinical description and diagnostic guidelines. Geneva: World Health Organization.
Williams HJ, Glaser B, Williams NM, Norton N, Zammit S, MacGregor S, et al
. (2005). No association between schizophrenia and polymorphisms in COMT in two large samples. Am J Psychiatry 162:1736-1738.
Wonodi I, Stine OC, Mitchell BD, Buchanan RW, Thaker GK (2003). Association between Val108/158 Met polymorphism of the COMT gene and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120B:47-50.
Wonodi I, Mitchell BD, Stine OC, Hong LE, Elliott A, Kirkpatrick B, et al.
(2006). Lack of association between COMT gene and deficit/nondeficit schizophrenia. Behav Brain Funct 2:42.
Woodward ND, Jayathilake K, Meltzer HY (2007). COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res 90:86-96.
[Table 1], [Table 2], [Table 3], [Table 4]