Schizophrenia, a severe psychiatric condition, is characterized by disturbances of cognition, emotion, and social functioning. The disease affects almost 1% of world population. Recent studies evaluating the role of catechol-O-methyltransferase enzyme (COMT) polymorphisms in the pathogenesis of schizophrenia have resulted in ambiguous findings. The current study examined the association of schizophrenia with three COMT polymorphisms, namely, rs737865, rs4680, and rs165599 in a Greek population. There was no significant association between schizophrenia and any of the three SNPs examined. However, haplotype analysis showed that cases have higher frequency of the T-A-A haplotype, and participants with that haplotype were at increased risk for developing schizophrenia (OR = 1.52; CL？:？1.12–2.08; ). Furthermore, patients with schizophrenia displayed an excess of TC/AA/AA and the TT/AA/GA genotypes. Similarly a protective effect of TT/GG/GG and TT/GA/GG was suggested by our results. 1. Background Schizophrenia is a severe, particularly devastating, psychiatric disorder affecting approximately 1% of the general population [1]. The disease is accompanied by significant social dysfunction. The onset of the symptoms usually occurs in young adulthood. Even though schizophrenia is highly heritable, the research for chromosomal loci and candidate genes has not provided any consistent results. Combinations of genetic, epigenetic, and environmental factors participate in the development of the disease. Since these factors have not been identified, the diagnosis of schizophrenia is based on phenotypic symptoms only [2]. Therefore, the identification of susceptibility genes is likely to provide valuable insights into the etiology and pathogenesis of the disease, consequently leading to the development of more effective treatments. Catechol-O-methyltransferase (COMT) is an enzyme, which catalyses the O-methylation of catecholamine neurotransmitters such as dopamine, adrenaline, and noradrenaline [3]. Disturbances in dopaminergic transmission have long been implicated in schizophrenia [4]. A “reformulated” hypothesis of the dopamine’s role in the disease states that hyperdopaminergic functioning in subcortical structures is associated with positive symptoms such as hallucinations and delusions, whereas hypodopaminergic functioning in prefrontal cortical regions is associated with negative and cognitive symptoms [5]. Dopamine is inactivated either by reuptake into the neurons that release dopamine into the synapse or through metabolism by monoamine oxidase or COMT. In
References
[1]
N. J. Bray and M. J. Owen, “Searching for schizophrenia genes,” Trends in Molecular Medicine, vol. 7, no. 4, pp. 169–174, 2001.
[2]
M. C. O'Donovan, N. M. Williams, and M. J. Owen, “Recent advances in the genetics of schizophrenia,” Human Molecular Genetics, vol. 12, no. 2, pp. R125–R133, 2003.
[3]
P. T. M？nnist？ and S. Kaakkola, “Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors,” Pharmacological Reviews, vol. 51, no. 4, pp. 593–628, 1999.
[4]
M. J. Owen, M. C. O'Donovan, and P. J. Harrison, “Schizophrenia: a genetic disorder of the synapse?” British Medical Journal, vol. 330, no. 7484, pp. 158–159, 2005.
[5]
K. L. Davis, R. S. Kahn, G. Ko, and M. Davidson, “Dopamine in schizophrenia: a review and reconceptualization,” American Journal of Psychiatry, vol. 148, no. 11, pp. 1474–1486, 1991.
[6]
A. Meyer-Lindenberg, T. Nichols, J. H. Callicott et al., “Impact of complex genetic variation in COMT on human brain function,” Molecular Psychiatry, vol. 11, no. 9, pp. 867–877, 2006.
[7]
T. M. Maynard, G. T. Haskell, J. A. Lieberman, and A. S. LaMantia, “22q11 DS: genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome,” International Journal of Developmental Neuroscience, vol. 20, no. 3–5, pp. 407–419, 2002.
[8]
K. C. Murphy, “Schizophrenia and velo-cardio-facial syndrome,” Lancet, vol. 359, no. 9304, pp. 426–430, 2002.
[9]
H. M. Lachman, D. F. Papolos, T. Saito, Y. M. Yu, C. L. Szumlanski, and R. M. Weinshilboum, “Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders,” Pharmacogenetics, vol. 6, no. 3, pp. 243–250, 1996.
[10]
T. Lotta, J. Vidgren, C. Tilgmann et al., “Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme,” Biochemistry, vol. 34, no. 13, pp. 4202–4210, 1995.
[11]
M. F. Egan, T. E. Goldberg, B. S. Kolachana et al., “Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6917–6922, 2001.
[12]
T. E. Goldberg, M. F. Egan, T. Gscheidle et al., “Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia,” Archives of General Psychiatry, vol. 60, no. 9, pp. 889–896, 2003.
[13]
T. Li, P. C. Sham, H. Vallada et al., “Preferential transmission of the high activity allele of COMT in schizophrenia,” Psychiatric Genetics, vol. 6, no. 3, pp. 131–133, 1996.
[14]
S. J. Glatt, S. V. Faraone, and M. T. Tsuang, “Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies,” American Journal of Psychiatry, vol. 160, no. 3, pp. 469–476, 2003.
[15]
M. R. Munafò, L. Bowes, T. G. Clark, and J. Flint, “Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies,” Molecular Psychiatry, vol. 10, no. 8, pp. 765–770, 2005.
[16]
M. F. Egan, T. E. Goldberg, B. S. Kolachana et al., “Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6917–6922, 2001.
[17]
S. Shifman, M. Bronstein, M. Sternfeld et al., “A highly significant association between a COMT haplotype and schizophrenia,” American Journal of Human Genetics, vol. 71, no. 6, pp. 1296–1302, 2002.
[18]
X. Chen, X. Wang, A. F. O'Neill, D. Walsh, and K. S. Kendler, “Variants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families,” Molecular Psychiatry, vol. 9, no. 10, pp. 962–967, 2004.
[19]
H. Y. Handoko, D. R. Nyholt, N. K. Hayward et al., “Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia,” Molecular Psychiatry, vol. 10, no. 6, pp. 589–597, 2005.
[20]
M. A. Palmatier, A. M. Kang, and K. K. Kidd, “Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles,” Biological Psychiatry, vol. 46, no. 4, pp. 557–567, 1999.
[21]
B. Funke, A. K. Malhotra, C. T. Finn et al., “COMT genetic variation confers risk for psychotic and affective disorders: a case control study,” Behavioral and Brain Functions, vol. 1, article no. 19, 2005.
[22]
B. A. Salisbury, M. Pungliya, J. Y. Choi, R. Jiang, X. J. Sun, and J. C. Stephens, “SNP and haplotype variation in the human genome,” Mutation Research—Fundamental and Molecular Mechanisms of Mutagenesis, vol. 526, no. 1-2, pp. 53–61, 2003.
[23]
S. E. Hyman and W. S. Fenton, “Medicine: what are the right targets for psychopharmacology?” Science, vol. 299, no. 5605, pp. 350–351, 2003.
[24]
N. J. Bray, P. R. Buckland, N. M. Williams et al., “A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain,” American Journal of Human Genetics, vol. 73, no. 1, pp. 152–161, 2003.
