Research update: COMT val158Met rs4680

Catechol-O-methyltransferase (COMT) is an enzyme which degrades catechols such as catecholamines (dopamine, adrenaline) and catecholestrogens (formed by cytochrome P450 in the liver). It catalyses the transfer of a methyl group from a donor compound (S adenosyl methionine, SAM) onto the oxygen of one of the hydroxyl groups, in the presence of Mg2+ (1).

COMT exist in two isoforms, a soluble and a membrane-bound form (S-COMT and MB-COMT, respectively). However, both are encoded on a single COMT gene, found on chromosome 22. The sequence of the two proteins is the same, with MB-COMT having an additional N-terminal section which tethers it to the membrane (2). Both isoforms catalyse the same reaction and have the same active site.

While S-COMT is most abundant in the liver, MB-COMT is predominantly expressed in the brain where it plays a role in dopamine inactivation (3). In some areas of the brain, dopamine transporters readily take up dopamine from the synaptic cleft into the pre-synaptic neuron to terminate the dopamine signal. However, in areas with extremely low levels of these transporters, such as the prefrontal cortex (PFC), COMT plays a much more important role in terminating dopaminergic transmission through dopamine degradation (4).

The rs4680 polymorphism is an extensively studied functional SNP of COMT. A change from G>A results in the conversion of a Valine to Methionine (Val158Met in MB-COMT). The Met allele is associated with a significant reduction in enzyme activity and decreased thermostability (5)(6).

Because of impaired enzyme activity, the Met allele is associated with higher extracellular dopamine levels in the PFC, as dopamine is not degraded as quickly (3). This presumably results in prolonged stimulation of the post-synaptic neuron and/or allows for greater dopamine availability at the synapse.

Memory

This affects influences prefrontal cognitive function, as the prefrontal cortex is an area important for working memory. The association between Val158Met and working memory seemed weak at first, as studies connecting V158Met and working memory have shown mixed results (7–10). However further research focusing on different types of working memory function showed that the SNP has no effect on cognitive processes that only require maintenance of information, but does affect processes demanding active manipulation or updating of information. The Met allele has found to be advantageous here, as it is associated with enhanced cognitive performance (11–15). Thus, Met allele carriers may hold an advantage in memory and attention tasks (16).

It is believed that there is an optimal intermediate level of dopamine at which prefrontal functioning is most efficient. Too much or too little dopamine seems to have negative effects on working memory. This can be thought of as an inverted-U shaped relationship between prefrontal dopamine levels and PFC performance. As the Met allele is related to higher PFC dopamine levels, Met homozygotes are thought to be closer to the optimum dopamine level on the inverted U curve than Val carriers (Fig 3).

Stress

In contrast, Met allele carriers tend to be more sensitive to biological stressors. Along with demonstrating a greater biological response to stressors (greater hypothalamic-pituitary-adrenal function, greater stress hormone response (17)), Met hetero- and homozygotes have been shown to subjectively experience greater stress in response to a task, compared to Val-homozygotes (18).

Val/val individuals have been shown to respond better to situations of acute and daily stress (19,20).

While Met homozygotes perform better on working memory tasks under no-stress conditions, working memory performance and cognitive function under acute stress is better for val homozygotes (21). It is believed that stress leads to increased release of dopamine and noradrenaline. This can be thought of as a shift to the right along the x-axis in figure 3. Under such conditions, individuals with Val alleles would benefit, having improved dopaminergic transmission and performance. Those with Met alleles would be at a detriment, as they would reach higher than optimal PFC dopamine levels.

There seems to be a trade-off between working memory performance and resiliency to stress. The function of COMT may make Met-carriers more sensitive to stress while improving cognitive performance.

Methylation

The rs4680 SNP is a G>A transition also abolishes a CpG site, where the cytosines are methylation sites. Each Val allele has one CpG methylation site and the Met allele has none. Val/val subjects with greater stress scores have reduced methylation at this site, and better working memory performance. This is most likely because methylation reduces COMT expression. Therefore, silencing of the COMT gene via methylation partially compensates for its negative effect on working memory. In Val/Met subjects, there was no relationship found between methylation, stress, prefrontal cognition, and COMT expression. (22)

Suggested dietary and lifestyle intervention

  • Reduce stress.
  • COMT requires magnesium in order to function properly. Consider increasing magnesium intake to maximise the COMT variant enzyme function.
  • COMT’s substrate is SAMe, the primary methyl donor for most methylation reactions. SAMe is a metabolite in the homocysteine-methionine cycle. It has been shown that an increase in dietary folate was associated with an increase (normalisation) of SAMe levels in those with previously low SAMe levels (23). Therefore, increasing folate intake could also help in optimising COMT activity.
  • Aside from metabolism by COMT, a second mechanism of dopamine clearance in the prefrontal cortex is the norepinephrine transporter. However, attempting to upregulate its function could have other negative consequences, since norepinephrine transporter inhibitors are drugs used to treat ADHD (24).

    • Further consideration

    The manifestation of a COMT allele as an observable phenotype is sometimes influenced by other genes. Deficits in multiple mechanisms produce more pronounced and reliable differences in stress response patterns than functional changes of a single component. These include 5-HTT and MAOA (25,26).

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