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Biological Basis of Sex Differences in Psychopharmacology pp 119–140Cite as

Importance of the COMT Gene for Sex Differences in Brain Function and Predisposition to Psychiatric Disorders

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Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 8))

Abstract

As outlined elsewhere in this volume, sex differences can affect brain function and its dysfunction in psychiatric disorders. It is known that genetic factors contribute to these sex dimorphisms, but the individual genes have rarely been identified. The catechol-O-methyltransferase (COMT) gene, which encodes an enzyme that metabolises catechol compounds, including dopamine, is a leading candidate in this regard. COMT’s enzyme activity, and the neurochemistry and behaviour of COMT knockout mice are both markedly sexually dimorphic. Furthermore, genetic associations between COMT and psychiatric phenotypes frequently show differences between men and women. Although many of these differences are unconfirmed or minor, some appear to be of reasonable robustness and magnitude and are reviewed in this chapter. Sexually dimorphic effects of COMT are usually attributed to transcriptional regulation by oestrogens; however, a careful examination of the literature suggests that additional mechanisms are likely to be at least as important. Here, we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes and brain function, and discuss potential mechanisms by which this may occur. We conclude that despite the evidence being incomplete, there are accumulating and in places compelling data showing that COMT has markedly sexually dimorphic effects on brain function and its dysfunction in psychiatric disorders. Although oestrogenic regulation of COMT is probably partially responsible for these sex differences, other mechanisms are likely also involved. Since sex differences in the genetic architecture of brain function and psychiatric disorders are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

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References

  • Abdolmaleky HM, Cheng KH, Faraone SV et al (2006) Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 15:3132–3145

    PubMed  CAS  PubMed Central  Google Scholar 

  • Aleman A, Kahn RS, Selten JP (2003) Sex differences in the risk of schizophrenia – evidence from meta-analysis. Arch Gen Psychiatry 60:565–571

    PubMed  Google Scholar 

  • Andersen SL, Teicher MH (2000) Sex differences in dopamine receptors and their relevance to ADHD. Neurosci Biobehav Rev 24:137–141

    PubMed  CAS  Google Scholar 

  • Babovic D, O'Tuathaigh CM, O'Sullivan GJ et al (2007) Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice. Behav Brain Res 183:236–239

    PubMed  CAS  Google Scholar 

  • Barnett JH, Heron J, Ring SM et al (2007a) Gender-specific effects of the catechol-O-methyltransferase Val(108)/(158)Met polymorphism on cognitive function in children. Am J Psychiatry 164:142–149

    PubMed  Google Scholar 

  • Barnett JH, Jones PB, Robbins TW et al (2007b) Effects of the catechol-O-ethyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 12:502–509

    PubMed  CAS  Google Scholar 

  • Barnett JH, Scoriels L, Munafò MR (2008) Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry 64:137–144

    PubMed  CAS  Google Scholar 

  • Barnett JH, Heron J, Goldman D et al (2009) Effects of catechol-O-methyltransferase on normal variation in the cognitive function of children. Am J Psychiatry 166:909–916

    PubMed  PubMed Central  Google Scholar 

  • Baron-Cohen S, Knickmeyer RC, Belmonte MK (2005) Sex differences in the brain: implications for explaining autism. Science 310:819–823

    PubMed  CAS  Google Scholar 

  • Baud P, Courtet P, Perroud N et al (2007) Catechol-O-methyltransferase polymorphism (COMT) in suicide attempters: a possible gender effect on anger traits. Am J Med Genet B Neuropsychiatr Genet 144B:1042–1047

    PubMed  CAS  Google Scholar 

  • Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812

    PubMed  CAS  Google Scholar 

  • Beuten J, Payne T, Ma J et al (2006) Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations. Neuropsychopharmacology 31:675–684

    PubMed  CAS  Google Scholar 

  • Biederman J, Kim JW, Doyle AE et al (2008) Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study. Am J Med Genet B Neuropsychiatr Genet 147B:1511–1518

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bilder RM, Volavka J, Lachman HM et al (2004) The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29:1943–1961

    PubMed  CAS  Google Scholar 

  • Bjornerem A, Straume B, Midtby M et al (2004) Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic diseases in a general population: the Tromso Study. J Clin Endocrinol Metab 89:6039–6047

    PubMed  CAS  Google Scholar 

  • Boudikova B, Szumlanski C, Maidak B et al (1990) Human liver catechol-O-methyltransferase pharmacogenetics. Clin Pharmacol Therap 48:381–389

    CAS  Google Scholar 

  • Bray N, Buckland P, Williams N et al (2003) A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73:152–161

    PubMed  CAS  PubMed Central  Google Scholar 

  • Briggs MH, Briggs M (1973) Hormonal influences on erythrocyte catechol-O-methyl transferase activity in humans. Experientia 29:278–280

    PubMed  CAS  Google Scholar 

  • Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7:477–484

    PubMed  CAS  Google Scholar 

  • Carroll ME, Lynch WJ, Roth ME et al (2004) Sex and estrogen influence drug abuse. Trends Pharmacol Sci 25:273–279

    PubMed  CAS  Google Scholar 

  • Caspi A, Moffitt TE, Cannon M et al (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 57:1117–1127

    PubMed  CAS  Google Scholar 

  • Chen JS, Lipska BK, Halim N 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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Cohn CK, Axelrod J (1971) The effect of estradiol on catechol-O-methyltransferase activity in rat liver. Life Sci 10:1351–1354

    CAS  Google Scholar 

  • Collaer ML, Hines M (1995) Human behavioral sex differences: a role for gonadal hormones during early development? Psychol Bull 118:55–107

    PubMed  CAS  Google Scholar 

  • Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62:847–855. doi:10.1016/j.biopsych.2007.03.001

    PubMed  CAS  PubMed Central  Google Scholar 

  • Craddock N, Owen MJ, O’Donovan MC (2006) The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol Psychiatry 11:446–58

    Google Scholar 

  • Creveling CR (2003) The role of catechol-O-methyltransferase in the inactivation of catecholestrogen. Cell Mol Neurobiol 23:289–291

    PubMed  CAS  Google Scholar 

  • Crowley WR, O'Donohue TL, Jacobowitz DM (1978) Changes in catecholamine content in discrete brain nuclei during the estrous cycle of the rat. Brain Res 147:315–326

    PubMed  CAS  Google Scholar 

  • Cutter WJ, Daly EM, Robertson DMW et al (2006) Influence of X chromosome and hormones on human brain development: a magnetic resonance imaging and proton magnetic resonance spectroscopy study of Turner syndrome. Biol Psychiatry 59:273–283

    PubMed  CAS  Google Scholar 

  • Dauvilliers Y, Neidhart E, Lecendreux M et al (2001) MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 6:367–372

    PubMed  CAS  Google Scholar 

  • Davies W, Wilkinson LS (2006) It is not all hormones: alternative explanations for sexual differentiation of the brain. Brain Res 1126:36–45

    PubMed  CAS  Google Scholar 

  • Dawling S, Roodi N, Mernaugh RL et al (2001) Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer Res 61:6716–6722

    PubMed  CAS  Google Scholar 

  • De Bellis J, Keshavan MS, Beers SR et al (2001) Sex differences in brain maturation during childhood and adolescence. Cereb Cortex 11:552–557

    PubMed  Google Scholar 

  • De Courten-Myers GM (1999) The human cerebral cortex: gender differences in structure and function. J Neuropathol Exp Neurol 58:217–226

    PubMed  Google Scholar 

  • De Vries GJ (2004) Sex differences in adult and developing brain: compensation, compensation, compensation. Endocrinol 145:1063–1068

    Google Scholar 

  • Dempster EL, Mill J, Craig IW et al (2006) The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC Med Genet 7:10

    PubMed  PubMed Central  Google Scholar 

  • Denys D, Van Nieuwerburgh F, Deforce D, Westenberg H (2006) Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive-compulsive disorder in males. Eur Neuropsychopharmacol 16:446–50

    Google Scholar 

  • Di Paolo T (1994) Modulation of brain dopamine transmission by sex steroids. Rev Neurosci 5:27–41

    PubMed  Google Scholar 

  • Domschke K, Freitag CM, Kuhlenbaumer G et al (2004) Association of the functional V158M catechol-O-methyltransferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 7:183–188

    PubMed  CAS  Google Scholar 

  • Domschke K, Deckert J, O’Donovan MC et al (2007) Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet 144B:667–673. doi:10.1002/ajmg.b.30494

    PubMed  CAS  Google Scholar 

  • Domschke K, Zavorotnyy M, Diemer J et al (2009) COMT val158met influence on electroconvulsive therapy response in major depression. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.30949

    Google Scholar 

  • Drabant EM, Hariri AR, Meyer-Lindenberg A et al (2006) Catechol O-methyltransferase val(158)met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry 63:1396–1406

    PubMed  CAS  Google Scholar 

  • Egan MF, Goldberg TE, Kolachana BS 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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Eley TC, Tahir E, Angleitner A et al (2003) Association analysis of MAOA and COMT with neuroticism assessed by peers. Am J Med Genet 120B:90–96

    PubMed  Google Scholar 

  • Enoch MA, Xu K, Ferro E et al (2003) Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr Genet 13:33–41

    PubMed  Google Scholar 

  • Enoch MA, Waheed JF, Harris CR et al (2006) Sex differences in the influence of COMT Val158Met on alcoholism and smoking in plains American Indians. Alcohol Clin Exp Res 30:399–406

    PubMed  CAS  Google Scholar 

  • Fahndrich E, Coper H, Christ W et al (1980) Erythrocyte COMT-activity in patients with affective disorders. Acta Psychiatrica Scand 61:427–437

    CAS  Google Scholar 

  • Fan JB, Zhang CS, Gu NF 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

    PubMed  CAS  Google Scholar 

  • Favis CF, Davis BF, Halaris AE (1977) Variations in the uptake of [3H] dopamine during the estrous cycle. Life Sci 20:1319–1332

    Google Scholar 

  • Fernandez-Ruiz JJ, Hernandez ML, De Miguel R et al (1991) Nigrostriatal and mesolimbic dopaminergic activities were modified throughout the ovarian cycle of female rats. J Neural Transm Gen Sect 85:223–229

    PubMed  CAS  Google Scholar 

  • Fitzgerald GA, Hamilton CA, Jones DH et al (1980) Erythrocytes catechol-O-methyltransferase activity and indices of sympathetic activity in man. Clin Sci 58:423–425

    PubMed  CAS  Google Scholar 

  • Floderus Y, Wetterberg L (1981) The inheritance of human erythrocyte catechol-O-methyltransferase activity. Clin Genet 19:392–393

    PubMed  CAS  Google Scholar 

  • Fullerton J, Cubin M, Tiwari H et al (2003) Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 72:879–890

    PubMed  CAS  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Gogos JA, Morgan M, Luine V et al (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 95:9991–9996

    PubMed  CAS  PubMed Central  Google Scholar 

  • Goldman-Rakic PS, Muly EC III, Williams GV (2000) D1 receptors in prefrontal cells and circuits. Brain Res Rev 31:295–301

    PubMed  CAS  Google Scholar 

  • Goldstein JM, Seidman LJ, Horton NJ et al (2001) Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex 11:490–497

    PubMed  CAS  Google Scholar 

  • Golimbet VE, Alfimova MV, Gritsenko IK et al (2007) Relationship between dopamine system genes and extraversion and novelty seeking. Neurosci Behav Physiol 37:601–606

    PubMed  CAS  Google Scholar 

  • Goodman JE, Jensen LT, He P et al (2002) Characterization of human soluble high and low activity catechol-O-methyltransferase catalyzed catechol estrogen methylation. Pharmacogenetics 12:517–528

    PubMed  CAS  Google Scholar 

  • Gothelf D, Eliez S, Thompson T et al (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci 8:1500–1502

    PubMed  CAS  Google Scholar 

  • Gray JA, McNaughton N (2000) The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 2nd edn. OUP, Oxford

    Google Scholar 

  • Gur RC, Mozley LH, Mozley PD et al (1995) Sex differences in regional cerebral glucose metabolism during a resting state. Science 267:528–531

    PubMed  CAS  Google Scholar 

  • Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase: a gene contributing to sex differences in brain function, and the sexual dimorphisms in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:3037–3045

    PubMed  CAS  Google Scholar 

  • Hoenicka J, Garrido E, Martínez I et al (2009) Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.30957

    Google Scholar 

  • Holmans P, Zubenko G, Crowe R et al (2004) Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am J Hum Genet 74:1154–1167

    PubMed  CAS  PubMed Central  Google Scholar 

  • Huotari M, Gogos JA, Karayiorgou M et al (2002a) Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15:246–256

    PubMed  Google Scholar 

  • Huotari M, Santha M, Lucas LR et al (2002b) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 303:1309–1316

    PubMed  CAS  Google Scholar 

  • Huotari M, Garcia-Horsman JA, Karayiorgou M et al (2004) d-amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice. Psychopharmacology 172:1–10

    PubMed  CAS  Google Scholar 

  • Jiang H, Xie T, Ramsden DB et al (2003) Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology 45:1011–1018

    PubMed  CAS  Google Scholar 

  • Jori A, Cecchetti G (1973) Homovanillic acid levels in rat striatum during the oestrus cycle. J Endocrinol 58:341–342

    PubMed  CAS  Google Scholar 

  • Kaasinen V, Nogren K, Hietala J et al (2001) Sex differences in extrastriatal dopamine D2-like receptors in the human brain. Am J Psychiatry 158:308–311

    PubMed  CAS  Google Scholar 

  • Kaminsky Z, Wang SC, Petronis A (2006) Complex disease, gender and epigenetics. Ann Med 38:530–544

    PubMed  CAS  Google Scholar 

  • Karayiorgou M, Altemus M, Galke BL et al (1997) Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA 94:4572–4575

    PubMed  CAS  PubMed Central  Google Scholar 

  • Karayiorgou M, Sobin C, Blundell ML et al (1999) Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 45:1178–1189

    PubMed  CAS  Google Scholar 

  • Karoum F, Chrapusta SJ, Egan MF (1994) 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 63:972–979

    PubMed  CAS  Google Scholar 

  • Katerberg H, Cath DC, Denys DA et al (2009) The role of the COMT Val(158)Met polymorphism in the phenotypic expression of obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.30971

    PubMed  Google Scholar 

  • Kates WR, Antshel KM, AbdulSabur N et al (2006) A gender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome). Am J Med Genet 141B:274–280

    PubMed  PubMed Central  Google Scholar 

  • Kelly SJ, Ostrowski NL, Wilson MA (1999) Gender differences in brain and behavior: hormonal and neural bases. Pharmacol Biochem Behav 64:655–664

    PubMed  CAS  Google Scholar 

  • Kempisty A, Mostowska A, G¢rska I et al (2006) Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett 400:267–271

    PubMed  CAS  Google Scholar 

  • Kempton MJ, Haldane M, Jogia J et al (2009) The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition: a fMRI study. Int J Neuropsychopharmacol 12:371–381

    PubMed  CAS  Google Scholar 

  • Kendler KS, Gatz M, Gardner CO et al (2006) A Swedish national twin study of lifetime major depression. Am J Psychiatry 163:109–114

    PubMed  Google Scholar 

  • Kim SJ, Kim YS, Kim SY et al (2006) An association study of catechol-O-methyltransferase and monoamine oxidase A polymorphisms and personality traits in Koreans. Neurosci Lett 401:154–158

    PubMed  CAS  Google Scholar 

  • Laakso A, Vilkman H, Bergman J et al (2002) Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects. Biol Psychiatry 52:759–763

    PubMed  CAS  Google Scholar 

  • Lachman HM, Papolos DF, Saito T et al (1996) Human catechol-o-methyltransferase polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

    PubMed  CAS  Google Scholar 

  • Lang UE, Bajbouj M, Sander T et al (2007) Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait. Neuropsychopharmacology 32:1950–1955

    PubMed  CAS  Google Scholar 

  • Lensi P, Cassano GB, Correddu G et al (1996) Obsessive-compulsive disorder. Familial-developmental history, symptomatology, comorbidity and course with special reference to gender-related differences. Br J Psychiatry 169:101–107

    PubMed  CAS  Google Scholar 

  • Lin PI, Vance JM, Pericak-Vance MA et al (2007) No gene is an island: the flip-flop phenomenon. Am J Hum Genet 80:531–538

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ma X, Sun J, Yao J et al (2007) A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. Psychiatry Res 153:7–15

    PubMed  CAS  Google Scholar 

  • Mannisto PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628

    PubMed  CAS  Google Scholar 

  • Mattay VS, Goldberg TE, Fera F 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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Meyer-Lindenberg A, Nichols T, Callicott JH et al (2006) Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11:877–882

    Google Scholar 

  • Mier D, Kirsch P, Meyer-Lindenberg A (2009) Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry. doi:10.1038/mp. 2009.36

    PubMed  Google Scholar 

  • Molero P, Ortuno F, Zalacain M et al (2007) Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J 7:418–426

    PubMed  CAS  Google Scholar 

  • Morissette M, Di Paolo T (1993) Sex and estrous cycle variations of rat striatal dopamine uptake sites. Neuroendocrinology 58:16–22

    PubMed  CAS  Google Scholar 

  • Mozley LH, Gur RC, Mozley PD et al (2001) Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 158:1492–1499

    PubMed  CAS  Google Scholar 

  • Munro CA, McCaul ME, Wong DF et al (2006) Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59:966–974

    PubMed  CAS  Google Scholar 

  • Murphy DGM, DeCarli C, McIntosh AR et al (1996) Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch Gen Psychiatry 53:585–594

    PubMed  CAS  Google Scholar 

  • Nackley A, Shabalina S, Tchivileva I et al (2006) Human catechol-O-methyl-transferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314:1930–1933

    PubMed  CAS  Google Scholar 

  • Nash MW, Huezo-Diaz P, Williamson RJ et al (2004) Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships. Hum Mol Genet 13:2173–2182

    PubMed  CAS  Google Scholar 

  • Nestadt G, Lan T, Samuels J et al (2000) Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Am J Hum Genet 67:1611–1616

    PubMed  CAS  PubMed Central  Google Scholar 

  • Nolan KA, Volavka J, Czobor P et al (2000) Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 10:117–124

    PubMed  CAS  Google Scholar 

  • O'Hara R, Miller E, Liao CP et al (2006) COMT genotype, gender and cognition in community-dwelling, older adults. Neurosci Lett 409:205–209

    PubMed  PubMed Central  Google Scholar 

  • Olsson CA, Anney RJ, Lotfi-Miri M et al (2005) Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 15:109–115

    PubMed  Google Scholar 

  • Ono H, Shirakawa O, Nushida H et al (2004) Association between catechol-O-methyltransferase functional polymorphism and male suicide completers. Neuropsychopharmacology 29:1374–1377

    PubMed  CAS  Google Scholar 

  • Oosterhuis BE, LaForge KS, Proudnikov D et al (2008) Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women. Am J Med Genet B Neuropsychiatr Genet 147B:793–798

    PubMed  CAS  PubMed Central  Google Scholar 

  • O'Tuathaigh CMP, Babovic D, O'Meara G et al (2007) Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. Neurosci Biobehav Rev 31:60–78

    PubMed  Google Scholar 

  • Patsopoulos NA, Tatsioni A, Ioannidis JP (2007) Claims of sex differences: an empirical assessment in genetic associations. JAMA 298:880–893

    PubMed  CAS  Google Scholar 

  • Pelayo-Terán JM, Crespo-Facorro B, Carrasco-Marín E et al (2008) Catechol-O-methyltransferase Val158Met polymorphism and clinical characteristics in first episode non-affective psychosis. Am J Med Genet B Neuropsychiatr Genet 147B:550–556

    PubMed  Google Scholar 

  • Philippu G, Hoo JJ, Milech U et al (1981) Catechol-O-methyltransferase of erythrocytes in patients with endogenous psychoses. Psychiatry Res 4:139–146

    PubMed  CAS  Google Scholar 

  • Piccinelli M, Wilkinson G (2000) Gender differences in depression – critical review. Br J Psychiatry 177:486–492

    PubMed  CAS  Google Scholar 

  • Pohjalainen T, Rinne JO, Nogren K et al (1998) Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo. Am J Psychiatry 155:768–773

    PubMed  CAS  Google Scholar 

  • Pooley EC, Fineberg N, Harrison PJ (2007) The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis. Mol Psychiatry 12:556–561

    PubMed  CAS  Google Scholar 

  • Poyurovsky M, Michaelovsky E, Frisch A, Knoll G, Amir I, Finkel B, Buniak F, Hermesh H, Weizman R (2005) COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study. Neurosci Lett. 389:21–4

    Google Scholar 

  • Preece P, Cairns NJ (2003) Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. Mol Brain Res 118:60–71

    PubMed  CAS  Google Scholar 

  • Qian Q, Wang Y, Zhou R, Li J, Wang B, Glatt S, Faraone SV (2003) Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Am J Med Genet B Neuropsychiatr Genet. 118B:103–9

    Google Scholar 

  • Quednow BB, Schmechtig A, Ettinger U et al (2009) Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study. Biol Psychiatry 66:614–620

    PubMed  CAS  PubMed Central  Google Scholar 

  • Robinson DS, Sourkes TL, Nies A et al (1977) Monoamine metabolism in human brain. Arch Gen Psychiatry 34:89–92

    PubMed  CAS  Google Scholar 

  • Rothe C, Koszycki D, Bradwejn J et al (2006) Association of the Val158Met caetchol-O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacol 31:2237–2242

    CAS  Google Scholar 

  • Rubinow DR, Schmidt PJ (1996) Androgens, brain, and behavior. Am J Psychiatry 153:974–984

    PubMed  CAS  Google Scholar 

  • Rybakowski JK, Borkowska A, Czerski PM et al (2006) Performance on the Wisconsin Card Sorting Test in schizophrenia and genes of dopaminergic inactivation (COMT, DAT, NET). Psychiatry Res 143:13–19

    PubMed  CAS  Google Scholar 

  • Salih SM, Salama SA, Jamaluddin M et al (2008) Progesterone-mediated regulation of catechol-O-methyl transferase expression in endometrial cancer cells. Reprod Sci 15(2):210–220

    PubMed  CAS  Google Scholar 

  • Sazci A, Ergul E, Kucukali I et al (2004) Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. Mol Brain Res 132:51–56

    PubMed  CAS  Google Scholar 

  • Sazci A, Ergul E, Kucukali I et al (2005) Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: association is significant in men but not in women. Progr Neuropsychopharmacol Biol Psychiatry 29:1113–1123

    CAS  Google Scholar 

  • Seeman MV (1997) Psychopathology in women and men: focus on female hormones. Am J Psychiatry 154:1641–1647

    PubMed  CAS  Google Scholar 

  • Shifman S, Bronstein M, Sternfeld M et al (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71:1296–1302

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shifman S, Bronstein M, Sternfeld M et al (2004) COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet Neuropsychiatr Genet 128B:61–64

    Google Scholar 

  • Shifman S, Johannesson M, Bronstein M et al (2008) Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4:e28

    PubMed  PubMed Central  Google Scholar 

  • Smolka MN, Schumann G, Wrase J et al (2005) Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci 25:836–842

    PubMed  CAS  Google Scholar 

  • Stein MB, Fallin MD, Schork NJ et al (2005) COMT polymorphisms and anxiety related personality traits. Neuropsychopharmacology 30:2092–2102

    PubMed  CAS  Google Scholar 

  • Stone JL, Merriman B, Cantor RM et al (2004) Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 75:1117–1123

    PubMed  CAS  PubMed Central  Google Scholar 

  • Strous RD, Ritsner MS, Adler S et al (2009) Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol 19:14–22

    PubMed  CAS  Google Scholar 

  • Sweet RA, Devlin B, Pollock BG et al (2005) Caetchol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. Mol Psychiatry 10:1026–1036

    PubMed  CAS  Google Scholar 

  • Talkowski ME, Kirov G, Bamne M et al (2008) A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet 17:747–758

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tammimäki A, Forsberg MM, Karayiorgou M et al (2008) Increase in free choice oral ethanol self-administration in catechol-o-methyltransferase gene-disrupted male mice. Basic Clin Pharmacol Toxicol 103:297–304

    PubMed  Google Scholar 

  • Tamminga CA (1997) Gender and schizophrenia. J Clin Psychiatry 58(suppl 15):33–37

    PubMed  Google Scholar 

  • Tan HY, Chen Q, Sust S et al (2007) Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proc Natl Acad Sci USA 104:12536–12541

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tsai SJ, Gau YT, Hong CJ et al (2009) Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients. Affect Disord 113:183–187

    CAS  Google Scholar 

  • Tunbridge EM, Bannerman DM, Sharp T et al (2004a) Catechol-O-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 24:5331–5335

    PubMed  CAS  Google Scholar 

  • Tunbridge E, Burnet PWJ, Sodhi MS et al (2004b) Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. Synapse 51:112–118

    PubMed  CAS  Google Scholar 

  • Tunbridge EM, Harrison PJ, Weinberger DR (2006a) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60:141–151

    PubMed  CAS  Google Scholar 

  • Tunbridge EM, Weinberger DR, Harrison PJ (2006b) A novel protein isoform of catechol O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val158Met genotype. Mol Psychiatry 11:116–117

    PubMed  CAS  Google Scholar 

  • Tunbridge EM, Weickert CS, Kleinman JE et al (2007a) Catechol-o-methyltransferase enzyme activity and protein expression in human prefrontal cortex across the postnatal lifespan. Cereb Cortex 17:1206–1212

    PubMed  CAS  Google Scholar 

  • Tunbridge EM, Lane TA, Harrison PJ (2007b) Expression of multiple catechol-o-methyltransferase (COMT) mRNA variants in human brain. Am J Med Genet Neuropsychiatr Genet 144B:834–839

    CAS  Google Scholar 

  • Tunbridge EM, Harrison PJ, Warden D et al (2008) Human plasma homocysteine levels are associated with the catechol-O-methyltransferase Val158Met polymorphism. Am J Med Genet B Neuropsychiatr Genet 147B:996–999

    PubMed  CAS  Google Scholar 

  • Vawter MP, Evans S, Choudary P et al (2004) Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes. Neuropsychopharmacology 29:373–384

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wang Z, Xiao Z, Inslicht SS et al (2009) Low expression of catecholamine-O-methyl-transferase gene in obsessive-compulsive disorder. J Anxiety Disord 23:660–664

    PubMed  Google Scholar 

  • Weinberger DR, Egan MF, Bertolino A et al (2001) Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825–844

    PubMed  CAS  Google Scholar 

  • Weiss LA, Pan L, Abney M et al (2006) The sex-specific genetic architecture of quantitative traits in humans. Nat Genet 38:218–222

    PubMed  CAS  Google Scholar 

  • Weiss EM, Stadelmann E, Kohler CG et al (2007) Differential effect of catechol-O-methyltransferase Val158Met genotype on emotional recognition abilities in healthy men and women. J Int Neuropsychol Soc 13:881–887

    PubMed  CAS  Google Scholar 

  • Williams NM, Glaser B, Norton N et al (2008) Strong evidence that GNB1L is associated with schizophrenia. Hum Mol Genet 17:555–566

    PubMed  CAS  Google Scholar 

  • Williams-Gray CH, Hampshire A, Robbins TW et al (2007) Catechol O-methyltransferase val158met genotype influences frontoparietal activity during planning in patients with Parkinson’s disease. J Neurosci 27:4832–4838

    PubMed  CAS  Google Scholar 

  • Woo J-M, Yoon K-S, Choi Y-H et al (2004) The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 38:365–370

    PubMed  Google Scholar 

  • Worda C, Sator MO, Schneeberger C et al (2003) Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reprod 18:262–266

    PubMed  CAS  Google Scholar 

  • Wray NR, James MR, Dumenil T et al (2008) Association study of candidate variants of COMT with neuroticism, anxiety and depression. Am J Med Genet B Neuropsychiatr Genet 147B:1314–1318

    PubMed  Google Scholar 

  • Xiao L, Becker JB (1994) Quantitative microdialysis determination of extracellular striatal dopamine concentration in male and female rats: effects of estrous cycle and gonadectomy. Neurosci Lett 180:155–158

    PubMed  CAS  Google Scholar 

  • Xie T, Ho SL, Ramsden D (1999) Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 56:31–38

    PubMed  CAS  Google Scholar 

  • Yavich L, Forsberg MM, Karayiorgou M et al (2007) Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J Neurosci 27:10196–10209

    PubMed  CAS  Google Scholar 

  • Zhang K, Zheng Z, Gao X et al (2007) Possible relationship between the COMT gene ValMet polymorphism and psychometric IQ in girls of the Qinba region in China. Neuropsychobiology 56:98–103

    PubMed  CAS  Google Scholar 

  • Zhu BT (2002) Catechol-O-methyltranferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab 3:321–329

    PubMed  CAS  Google Scholar 

  • Zinkstok J, Schmitz N, van Amelsvoort T et al (2006) The COMT val158met polymorphism and brain morphometry in healthy young adults. Neurosci Lett 405:34–39

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Daniel Weinberger for insightful discussions and fruitful collaborations. Valerie West kindly provided secretarial assistance. E.M.T. is supported by a Royal Society Research Fellowship. We apologise to authors of relevant studies that we have inadvertently omitted.

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  1. Department of Psychiatry, University of Oxford, Neurosciences Building, Warneford Hospital, Oxford, OX3 7JX, UK

    Elizabeth M. Tunbridge & Paul J. Harrison

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  1. Elizabeth M. Tunbridge
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  2. Paul J. Harrison
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  1. Bradford School of Pharmacy, University Bradford, Bradford, W.Yorkshire, BD7 1DP, United Kingdom

    Jo C. Neill

  2. Monash Alfred Psychiatry Research Centre, Commercial Rd., Melbourne, 3004, Australia

    Jayashri Kulkarni

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Tunbridge, E.M., Harrison, P.J. (2010). Importance of the COMT Gene for Sex Differences in Brain Function and Predisposition to Psychiatric Disorders. In: Neill, J., Kulkarni, J. (eds) Biological Basis of Sex Differences in Psychopharmacology. Current Topics in Behavioral Neurosciences, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2010_97

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