Biochemical functioning of neurons within the human brain is often studied using contemporary neuroimaging methods such as magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). But sometimes we are hindered in our ability to study a particular process within neurons themselves and must turn to more accessible cells such as those found circulating within the bloodstream. Examples relevant to neuropharmacology include the study of β-adrenergic receptors in lymphocytes (a major family of white blood cells), MAO in blood platelets, and, for the present discussion, COMT in red blood cells. As far back as the 1970s, researchers noticed a large amount of variability in COMT activity (i.e., the rate of catecholamine O-methylation) in red blood cells obtained from different healthy human subjects. However, the source of this variability remained unknown until the report by Lachman and coworkers (1996) of variation in the COMT gene. Most genes have multiple alleles (different forms of the gene), which together comprise genetic polymorphisms (the word “polymorphism” from “poly,” meaning many, and “morph,” which means form). An important class of genetic polymorphisms is single nucleotide polymorphisms (SNPs), which consist of differences at a single nucleotide at a particular position in the DNA sequence. If the change in that nucleotide causes a different amino acid to be synthesized at that position in the protein coded for by the gene, then the protein may undergo a functional change (e.g., a SNP in a gene that codes for an enzyme could be associated with differences in enzymatic activity).
The genetic variation discovered in the COMT gene was, indeed, a SNP that coded for substitution of the amino acid methionine (Met) for valine (Val) at codon 158 of the COMT gene (designated Val158Met). This single amino acid substitution causes the COMT enzyme to be less stable at normal body temperature, thus leading to significantly lower enzyme activity in individuals carrying the Met allele of the gene. Importantly, this difference is manifested not only in red blood cells, where it was first discovered, but also in the brain. In the striatum, where the DA transporter is abundantly expressed, rapid DA reuptake is the principal mechanism by which dopaminergic transmission is terminated. However, expression of this transporter is much lower in the prefrontal cortex (PFC), as a result of which COMT-mediated inactivation is a key mode of terminating DA signaling in the PFC (Käenmäki et al., 2010). Consequently, individuals possessing the Met allele of the COMT gene are believed to have enhanced dopaminergic transmission in the PFC due to the slower DA metabolism.
Since its discovery, the Val158Met SNP has become one of the most intensively studied genetic polymorphisms in neuropsychiatry. Among the reasons for this interest are the hypothesized involvement of DA in various neuropsychiatric disorders, and also its ability (especially in the PFC) to modulate cognitive processes that are dysfunctional in many of these same disorders (see textbook Box 12.2 for additional discussion). We will first discuss evidence implicating COMT in cognition, after which we will turn our attention to research that has examined whether the Val158Met SNP has been linked with schizophrenia, depression, or anxiety disorders.
The influence of COMT activity on cognitive function has been examined in several studies using transgenic mice. Strains of mice engineered to overexpress COMT (either the mouse gene or a human transgene with the Val allele) exhibited impaired working memory, supporting the hypothesis that higher rates of DA breakdown (as occur in homozygous Val/Val individuals) have an adverse effect on at least some cognitive processes (Papaleo et al., 2008; Simpson et al., 2014). Consistent with the effects of COMT overexpression, mice with a null mutation of the COMT gene showed enhanced working memory (Papaleo et al., 2008). However, it is important to note that the above findings were obtained with male mice. A later study of female COMT knockout mice found poorer instead of enhanced working memory (Sannino et al., 2015). The reason why females do not show the same relationship as males between COMT activity and working memory is unknown at this time.
Human studies of the Val158Met polymorphism and executive function/cognition have been performed both with healthy control participants and with individuals diagnosed with various psychiatric disorders. This research has yielded mixed results. For example, a review published several years ago concluded that possession of the Met allele conferred improved working memory performance in patients with schizophrenia but not in healthy control participants (Ira et al., 2013). A recent study additionally found better memory performance in Met allele carriers (compared to those with a Val/Val genotype) who had been diagnosed with posttraumatic stress disorder (PTSD) but not in healthy controls (Mestrovic et al., 2018). In contrast, Sannino and coworkers (2015) found that control male but not female Met carriers showed better working memory than Val/Val carriers. As in the case of the previously discussed mouse studies, this finding emphasizes the importance of testing for sex differences when assessing the effects of the Val158Met polymorphism on cognitive function.
A different line of research has examined whether the Val158Met polymorphism is associated with risk for developing a neuropsychiatric disorder. The underlying premise for this work is that variation in dopaminergic signaling could either cause differences in disease risk or simply predict risk without having a causal role. Recent meta-analyses of this literature have concluded that possession of one or two copies of the Met allele (and, therefore, having a slower rate of DA metabolism) reduces the risk of developing schizophrenia, panic disorder, and major depression, but it increases the risk for obsessive-compulsive disorder and bipolar depression (Gatt et al., 2015; González-Castro et al., 2016; Howe et al., 2016; Wang et al., 2016). Interestingly, these effects seem to be present in Caucasian (European ancestry) but not Asian individuals. This likely means that genetic differences between these ethnic groups interact with the COMT polymorphism to influence risk for neuropsychiatric illness.
The last area of research on this polymorphism concerns its effect on responsiveness to dopaminergic drugs. Investigators have studied moderation of the behavioral and therapeutic effects of psychostimulants (used to treat attention deficit hyperactivity disorder), the COMT inhibitor tolcapone (used as an adjunct medication for Parkinson’s disease), and DA D2 receptor antagonists (used as antipsychotic medications). Of these three different types of drugs, the most consistent evidence is that possession of one or two Met alleles confers greater effectiveness of antipsychotic drugs to improve positive symptoms in patients with schizophrenia (Huang et al., 2016) and to enhance cognitive functioning in patients with schizophrenia or other psychotic disorders (Schact, 2016).
Taken together, these findings illustrate how a genetically-mediated change in a single amino acid in a single neurotransmitter metabolizing enzyme can exert widespread effects on behavior, vulnerability to developing a neuropsychiatric disorder, and sensitivity to the therapeutic benefits of drug medications. Admittedly, experimental findings are often inconsistent or may be restricted to a specific sex or ethnic group. However, this is not surprising since genes do not act in isolation but rather exert their effects through an interactional process with other genes as well as numerous environmental factors.
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