1. ¹Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands
2. ²Department of Clinical Genetics, Section of Medical Genomics, VU Medical Center, Vrije Universiteit, Amsterdam, The Netherlands
3. ³Center for Neurogenomics and Cognitive Research – CNCR, Vrije Universiteit, Amsterdam, The Netherlands
4. ⁴Department of Child and Adolescent Psychiatry, Erasmus University Rotterdam, Rotterdam, The Netherlands

Correspondence: Dr M Florencia Gosso, Department of Biological Psychology, Vrije Universiteit, Van der Boechorststraat 1, Amsterdam 1081 BT, The Netherlands. Tel: +31 20 5988793; Fax: +31 20 5988832; E-mail: mf.gosso@vumc.nl

Received 21 August 2007; Revised 5 January 2008; Accepted 5 February 2008; Published online 2 April 2008.

Abstract

The COMT Val^108/158Met 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^108/158Met 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.