Catechol O-methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene–gene interaction on working memory functioning

Abstract

The COMT Val 108/158 Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val 108/158 Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account.

Association Between Polymorphisms of the Dopamine Receptor D2 and Catechol-o-Methyl Transferase Genes and Cognitive Function

“…Met:Met isoform was also associated with episodic memory and recall, but not with semantic memory, fluency, or knowledge (de Frias et al 2004); as well as with improved executive function, measured by verbal fluency, working memory, and Tower of Hanoi (de Frias et al 2005). However, subjects with the Val:Met isoform have also been found to have better performance on memory tasks over homozygotes (Gosso et al 2008;Harris et al 2005). There have also been findings of no association between COMT and performance on a range of other cognitive tests (O'Hara et al 2006;Ho et al 2005;Reuter et al 2005).…”

“…Differences in study results may be due to differences in age, as well as other potential interactions as few studies were in generally healthy populations. It has previously been found that an interaction between the activity of COMT and the expression of dopamine receptors such as DRD2 has an effect on cognitive function (Gosso et al 2008;Reuter et al 2005;Xu et al 2007). …”

“…The DRD2 densities or activities have also been found to decrease with age (Fetsko et al 2005;Kaasinen and Rinne 2002), and decreased DRD2 binding, as well as levels of dopamine available, have been associated with decreased cognitive function (Cropley et al 2006). It has also been demonstrated that there is an inverted-U relationship between dopamine signalling in the prefrontal cortex (PFC) and cognitive ability, with both low and excessive dopamine activity in the PFC decreasing a range of cognitive abilities (Savitz et al 2006;Harris et al 2005;Turnbridge et al 2006;Gosso et al 2008). This is likely to be affected by both the level of dopamine available, altered in part by expression and catabolism, and by dopamine receptor availability and binding potential.…”

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…First off, regarding fronto-striatal genetics, gene-gene interactive effects between the COMT polymorphism and the TaqIA-ANKK1 polymorphism are consistently reported in working memory tasks (Reuter et al, 2005;Gosso et al, 2008;Stelzel et al, 2009Stelzel et al, , 2010Garcia-Garcia et al, 2011;Wishart et al, 2011;Berryhill et al, 2013). Two studies reported higher stability and accuracy of task-relevant representations during delays and lower interference in Met/A1 carriers compared to Val/A1 carriers.…”

Heterozygote Advantage of the MTHFR C677T Polymorphism on Specific Cognitive Performance in Elderly Chinese Males without Dementia

“…The condition in which heterozygotes show better functioning than homozygotes for quantitative traits is usually referred to as positive heterosis. Positive heterosis is common in humans and has been reported for the influence on cognitive function of the catechol O-methyl transferase genetic polymorphism [21]. An earlier study demonstrated a lower proportion of MTHFR C677T heterozygotes among the mothers of nonsyndromic cleft lip probands, showing a heterozygote advantage [22].…”