Catechol-O-methyltransferase (COMT) polymorphism and Cognition
Since the mapping of the human genome, a field called neuropsychiatric phenomics has emerged, which integrates genetic data with neurobiology and cognitive neuroscience. One single-nucleotide polymorphism (SNP) on chromosome 22 has received considerable attention over the last two decades for its role in cognition (i.e., the COMT Val158Met polymorphism). This COMT gene codes for the enzyme, catechol-o-methyltransferase, which plays a role in the clearance of catecholamines such as dopamine. The COMT enzyme is believed to be especially important for clearance of dopamine within the prefrontal cortex (PFC). Some individuals are born with COMT enzymes that slowly remove dopamine from the PFC (Val/Val homozygotes), and others with COMT enzymes that rapidly remove dopamine from the PFC (Met/Met homozygotes). Research comparing individuals with slow versus fast variants of the COMT gene has repeatedly demonstrated that people with the slow acting COMT enzyme have greater amounts of dopamine within the PFC. These individuals tend to perform better on cognitive measures, particularly measures which assess executive functioning. These findings have been replicated several times in neurologically normal children and adults, and in adult patients with schizophrenia.
WEBINAR: COMT and Schizophrenia
Professor Daniel Weinberger explains why the gene COMT, which catabolizes dopamine, is a candidate gene for schizophrenia.
ABSTRACT: Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects (2014)
The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age.
Carmel, M., Zarchi, O., Michaelovsky, E., Frisch, A., Patya, M., Green, T., Gothelf, D., & Weizman, A. (2014) Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects. J Psychiatr Res, 56, 28-35. doi: 10.1016/j.jpsychires.2014.04.019.
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 phenotypes. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 29(11), 1943–61. doi:10.1038/sj.npp.1300542
Nolan, K. A., Bilder, R. M., Lachman, H. M., & Volavka, J. (2004). Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility. The American journal of psychiatry, 161(2), 359–61. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14754787
Yeh, T., Chang, C., Hu, C., Yeh, T., & Lin, M. (2009). Association of catechol-O-methyltransferase (COMT) polymorphism and academic achievement in a Chinese cohort. Brain Cogn, 3, 300-5. doi: 10.1016/j.bandc.2009.07.011.