The recent studies of Prata and colleagues and Roffman and colleagues shed considerable further light on the ongoing mysteries of the catechol-O-methyltransferase Val158Met polymorphism and its effects on the proposed “inverted-U” shape of cortical dopamine function. Both study teams should be congratulated on these high-quality studies using what are, for neuroimaging experiments, impressive numbers of both patients and controls.

Our understanding of the effects of the COMT Val/Met polymorphism in humans remains incomplete despite no shortage of elegant studies and intriguing results. In their landmark 2001 paper, Egan and colleagues reported that Val carriers showed poorer cognitive function, a higher risk for schizophrenia, and reduced prefrontal efficiency when compared with Met carriers. These associations, along with a multitude of other psychological and psychiatric phenotypes, have since been tested in labs across the world. Meta-analyses of the available data have concluded that there is little influence of the Val/Met polymorphism on risk for schizophrenia (Allen et al., 2008; Fan et al., 2005; Munafo et al., 2005) or cognitive function (Barnett et al., 2008). Perhaps because of the increased cost and difficulty of collecting imaging data compared with cognitive or disease status, rather fewer studies have been published testing the hypothesis that Val/Met affects prefrontal cortical efficiency, but those few (e.g., Ho et al., 2005) do appear consistent with the original report .

Prata et al. (2008) studied the effects of Val/Met on cortical activation during a verbal fluency task and report an interesting, if somewhat unintuitive result: that there are opposite effects of genotype on task performance and cortical activation in patients with schizophrenia, compared with those seen in healthy controls. In patients, Val alleles were associated with poorer task performance, while in controls, there was no significant difference between genotype groups. The trend, however, was for better task performance among Val-carrying controls, and the group x genotype interaction term was significant. These results were interestingly reflected in regional activation patterns, where in the right peri-Sylvian region Val alleles were associated with increased activation in patients, and decreased activation in controls. Further analyses suggested that these group x genotype interactions may partly reflect genetically driven differences in functional connectivity. Explanations for these opposite effects in patients and controls are consistent with an inverted-U shape of dopaminergic function where patients lie on the left-hand side of the U (suboptimal dopamine) and controls lie somewhat to the right of the center, such that increased cortical dopamine (as experienced by Met carriers) is slightly disadvantageous. Interestingly, we found the same pattern when comparing the effect of Val/Met genotype on N-back performance in patients and controls (Barnett et al., 2008); it is good to see these non-linear behavioral results supported by structural and functional imaging data.

The Val/Met polymorphism is certainly not the only determinant of COMT function, and we now know that other SNPs within the gene greatly affect the amount of COMT expressed (Nackley et al., 2006). Moreover, in affecting cortical dopamine and norepinephrine, COMT does not operate alone. Roffman and colleagues’ study (Roffman et al., 2008) very nicely demonstrates how much we have still to learn about potential gene-gene interaction (epistatic) effects. They studied brain activation during a working memory task and analyzed the combined effects of Val/Met and a functional polymorphism in MTHFR, a gene with plausible biological interactions with COMT. In this study, COMT genotype alone did not predict variation in activation in dorsolateral prefrontal cortex. There was a three-way interaction, however, between COMT and MTHFR genotypes and diagnostic group, such that MTHFR genotype appeared to modulate prefrontal activation most in Val/Val patients (who would be expected to have the lowest prefrontal dopamine), and among Met/Met controls (who would be expected to have the highest prefrontal dopamine, potentially putting them beyond the optimal level in the inverted-U model).

Despite considerable interest in gene-gene and gene-environment interactions among schizophrenia researchers, replications of such interactions have been relatively few and far between. While it is notoriously difficult to demonstrate biological interaction from statistical data alone, Roffman’s study provides us with hope that a really good hypothesis may still give us reason to try and do so.

References:

Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet. 2008 Jul 1;40(7):827-34. Abstract

Barnett JH, Scoriels L, Munafò MR. Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry. 2008 Jul 15;64(2):137-44. Abstract

Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry. 2005 Jan 15;57(2):139-44. Abstract

Ho BC, Wassink TH, O'Leary DS, Sheffield VC, Andreasen NC. Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry. 2005 Mar 1;10(3):229, 287-98. Abstract

Munafò MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug 1;10(8):765-70. Abstract

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006 Dec 22;314(5807):1930-3. Abstract

Prata DP, Mechelli A, Fu CH, Picchioni M, Kane F, Kalidindi S, McDonald C, Howes O, Kravariti E, Demjaha A, Toulopoulou T, Diforti M, Murray RM, Collier DA, McGuire PK. Opposite Effects of Catechol-O-Methyltransferase Val158Met on Cortical Function in Healthy Subjects and Patients with Schizophrenia. Biol Psychiatry. 2008 Dec 1; Abstract

Roffman JL, Gollub RL, Calhoun VD, Wassink TH, Weiss AP, Ho BC, White T, Clark VP, Fries J, Andreasen NC, Goff DC, Manoach DS. MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met. Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17573-8. Abstract

View all comments by Jennifer Barnett

  I recommend the Primary Papers

The “inverted-U” shape of cortical dopamine function with regard to the COMT Val158Met polymorphism is an interesting issue worthy of discussion. The COMT enzyme may modulate the balance of tonic and phasic dopamine function depending on the area-specific neurochemical environment (Bilder et al., 2004). There is thought to be a complex nonlinear relationship between dopamine availability and brain function (Williams et al., 2007).

Our study (Liao et al., 2008) examined the relationships of three COMT SNPs—rs737865 in intro 1, rs4680 in exon 4 (Val158Met), and downstream rs165599—to schizophrenia and its related deficits in neurocognitive function in families of patients with schizophrenia in Taiwan. The study results indicated that the Val allele was associated with better performance on the WCST (i.e., greater Categories Achieved and Conceptual Level Response and fewer Perseverative Errors) or CPT (i.e., greater d'), which might be explained by an “inverted U” shaped relationship between dopamine levels and prefrontal cortex function (Cools and Robbins 2004; Mattay et al., 2003). This model reveals that an optimal functioning occurs within a narrow range of dopamine level, and both excessive and insufficient dopamine levels impair working memory performance. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions, hence conferring increased risk to schizophrenia.

References:

Bilder, R.M., Volavka, J., Lachman, H.M. & Grace, A.A. (2004) The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric pheno-types. Neuropsychopharmacology 29, 1943–1961. Abstract

Cools, R. and Robbins, T.W. (2004) Chemistry of the adaptive mind. Philos Transact A Math Phys Eng Sci 362, 2871–2888. Abstract

Liao S.Y., Lin S.H., Liu C.M., Hsieh M.H., Hwang T.J., Liu S.K., Guo S.C., Hwu, H.G., Chen W.J. (2008): Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia. Genes, Brain and Behavior. Abstract

Mattay, V.S., Goldberg, T.E., Fera, F., Hariri, A.R., Tessitore, A., Egan, M.F., Kolachana, B., Callicott, J.H. and Weinberger, D.R. (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100, 6186–6191. Abstract

Williams, H.J., Owen, M.J. and O‘Donovan, M.C. (2007) Is COMT a susceptibility gene for schizophrenia? Schizophr Bull 33, 635–641. Abstract

View all comments by S.H. Lin