Skip to main content Accessibility help

Warriors Versus Worriers: The Role of COMT Gene Variants

  • Dan J. Stein, Timothy K. Newman, Jonathan Savitz and Rajkumar Ramesar


Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance. while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.



Hide All
1.Stein, DJ, Moeller, FG. The man who turned bad. CNS Spectr. 2005;10:8890.
2.Chambers, RA, Taylor, JR, Potenza, MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry. 2003;160:10411052.
3.Stein, DJ, Hollander, E. Impulsive aggression and obsessive-compulsive disorder. Psychiatr Ann. 1993;23:389395.
4.Stein, DJ. Neurobiology of the obsessive-compulsive spectrum disorders. Biol Psychiatry. 2000;47:296304.
5.Winterer, G, Musso, F, Vucurevic, G, et al.COMT genotype predicts BOLD signal and noise characteristics in prefrontal circuits. Neuroimage. 2006 Jul 31; [Epub ahead of print].
6.Egan, MF, Goldberg, TE, Kolachana, BS, et al.Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA. 2001;98:69176922.
7.Goldberg, TE, Egan, MF, Gscheidle, T, et al.Executive subprocesses in working memory: relationship to catectiol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry. 2003;60:889896.
8.Blasi, G, Mattay, VS, Bertolino, A, et al.Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci. 2005;25:50385045.
9.Bishop, SJ, Cohen, JD, Fossella, J, et al.COMT genotype influences prefrontal response to emotional distraction. Cogn Affect Behav Neurosci. 2006;6:6270.
10.Zubieta, JK, Heitzeg, MM, Smith, YR, et al.COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:12401243.
11.Smolka, MN, Schumann, G, Wrase, J, et al.Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci. 2005;25:836842.
12.Kates, WR, Antshel, KM, Abdulsabur, N, et al.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 B Neuropsychiatr Genet. 2006;141:274280.
13.Zinkstok, J, Schmitz, N, van Amelsvoort, T, et al.The COMT val(158)met polymorphism and brain morphometry in healthy young adults. Neurosci Lett. 2006;405:3439.
14.Meyer-Lindenberg, A, Kohn, PD, Kolachana, B, et al.Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005;8:594596.
15.Bilder, RM, Volavka, J, Czobor, P, et al.Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry. 2002;52:701707.
16.Malhotra, AK, Kestler, LJ, Mazzanti, C, et al.A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry. 2002;159:652654.
17.Heinz, A, Smolka, MN. The effects of catechol 0-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks. Rev Neurosci. 2006;17:359367.
18.Xu, K, Ernst, M, Goldman, D. Imaging genomics applied to anxiety, stress response, and resiliency. Neuroinformatics. 2006;4:5164.
19.Tunbridge, EM, Harrison, PJ, Weinberger, DR. Catechol-o-Methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006;60:141151.
20.Olsson, CA, Anney, RJ, Lotfi-Miri, M, et al.Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet. 2005;15:109115.
21.Diatchenko, L, Slade, GD, Nackley, AG, et al.Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14:135143.
22.McGrath, M, Kawachi, I, Ascherio, A, et al.Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry. 2004;161:17031705.
23.Munafo, MR, Bowes, L, Clark, TG, et al.Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005;10:765770.
24.Mattay, VS, Goldberg, TE, Fera, Fet al.Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA. 2003;100:61866191.
25.Caspi, A, Moffitt, TE, Cannon, M, et al.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. 2005;57:11171127.
26.Mill, J, Dempster, E, Caspi, A, et al.Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am J Med Genet B Neuropsychiatr Genet. 2006;141:421425.
27.van Praag, HM, Asnis, GM, Kahn, RS, et al.Monoamines and abnormal behaviour. A multi-aminergic perspective. Br J Psychiatry. 1990;157:723734.
28.Weickert, TW, Goldberg, TE, Mishara, A, et al.Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry. 2004;56:677682.
29.Arias, B, Serretti, A, Lorenzi, C, et al.Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin. J Affect Disord. 2006;90:251256.
30.Bertolino, A, Caforio, G, Blasi, G, et al.Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry. 2004;161:17981805.
31.Lee, MS, Kim, HS, Cho, EK, et al.COMT genotype and effectiveness of entacapone in patients with fluctuating Parkinson's disease. Neurology. 2002;58:564567.
32.Yamanouchi, Y, Iwata, N, Suzuki, T, et al.Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 2003;3:356361.
33.Rakvag, TT, Klepstad, P, Baar, C, et al.The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain. 2005;116:7378.
34.Craddock, N, Owen, MJ, O'Donovan, MC. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol Psychiatry. 2006;11:446458.
35.De Luca, V, Tharmalingam, S, Sicard, T, Kennedy, JL. Gene-gene interaction between MAOA and COMT in suicidal behavior. Neurosci Lett. 2005;383:151154.
36.Zahn-Waxler, C. Warriors and worriers: gender and psychopathology. Dev Psychopathol. 1993;5:7989.
37.Brook, JS, Whiteman, M, Cohen, P. Warriors and worriers: a longitudinal study of gender differences in drug use. NIDA Research Monographs. 2000;271284.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed