An association study of DRD2 and COMT polymorphisms with novelty seeking and harm avoidance scores, in two independent samples of depressed patients

Reuter et al. [1] recently reported that the dopamine D2 receptor (DRD2) and catechol-O-methyltransferase (COMT) genes are associated with variation in individuals' behavioural approach system. The DRD2 TaqI A1 and COMT Val alleles were not individually associated with behaviour, yet an interaction of the loci significantly predicted differences in response. An individual's behavioural approach system (BAS), as well as their behavioural inhibition system (BIS), were assessed using Carver and White's [2] BIS/BAS scales. The BAS represents an individual's sensitivity to appetitive stimuli, such as reward or avoidance of punishment [2]. Meanwhile, the BIS comprises an individual's inhibition towards goals due to sensitivity to aversive stimuli or extreme novelty [2]. Reuter et al. [1] found that higher BAS scores, in particular on the 'Drive' and 'Fun-seeking' scales, were observed in those with Val-/A1- or Val+/A1+ genotype. No support was found for an effect of these gene loci on the individuals' BIS scores [1]. Gender had a significant effect on BIS scores, both as an independent variable and in association with the presence/absence of the COMT Met allele. Men possessing the COMT Met allele had lower BIS scores than men without this allele, whilst the inverse pattern occurred amongst women [1].

DRD2 and COMT have been investigated as candidate genes for behaviour motivation because of their essential roles within the dopamine system. The enzymatic activity of COMT is attenuated by the occurrence of a single nucleotide polymorphism (G>A) which causes an amino acid substitution (from a valine (Val) to a methionine (Met) residue) at codon 158 [3]. The DRD2 TaqIA polymorphism is a single nucleotide transition which creates a restriction fragment polymorphism [4]. The A1 allele has been associated with a 30–40% reduction in D2 dopamine receptor density, compared to individuals homozygous for the A2 allele [5–8]. Both polymorphisms have been associated with measures of behavioural motivation, including Cloninger's harm avoidance (HA) and novelty seeking (NS) scales. Enoch et al. [9] found that females homozygous for the COMT Met allele reported the highest HA scores. Within two samples of young males, the presence of the DRD2 TaqI A1 polymorphism was associated with increased NS [10, 11].

Carver and White's [2] BIS/BAS scales represent the operationalisation of Jeffrey Gray's Reinforcement Sensitivity Theory. Gray and Cloninger's personality models are conceptually equivalent [2]. They both theorise that human behaviour is based on an interplay of at least two biological self-regulatory systems – one which is responsive to aversive stimuli (BIS or HA) and the other to appetitive stimuli (BAS or NS). Concordantly, positive associations have been found between HA and BIS, and NS and the BAS fun-seeking scale [2, 12]. This paper reports our finding that DRD2 and COMT are not associated with behavioural activation in two independent Caucasian samples of depressed patients assessed with Cloninger's Temperament and Character Inventory (TCI) [13].

We found no support for an association of DRD2 TaqI A and COMT Val polymorphisms with an individual's behavioural approach response, using the TCI NS scale in two samples of depressed patients. The effect size associated with the presence of either the A1 or Val allele on NS scores was very small (<0.18) providing strong evidence that the lack of association was not the result of inadequate statistical power. This contrasts with Reuter et al.'s [1] findings that these genes epistatically influence fun-seeking scores – which are correlated with TCI NS scores. Consistent with our findings, Enoch et al. [9] found that the COMT Val polymorphism was not associated with NS in either a Caucasian or an American Indian community sample. In contrast, Tsai et al. [19] in a sample of Chinese female nursing students found that individuals homozygous for the Val allele had higher NS [19]. Noble et al. [10] reported a significant association of NS with the DRD2 TaqI A polymorphism and DRD2 haplotype (TaqI A, TaqI B and intron 6 polymorphisms), although the association was significant for only one NS subscale. Conversely, Lee et al. [20] found no association between these three DRD2 polymorphisms and NS or HA scores, within a young Korean sample. Investigating two other DRD2 polymorphisms – Ser311Cys and -141Ins/del – within an Austrian and Japanese sample, Gebhardt et al. [21] and Katsuragi et al. [22], respectively, found no support for an association with either NS or HA.

We found no association of DRD2 and COMT polymorphisms with individuals' behavioural inhibition – based on TCI HA scores – consistent with Reuter et al. [1]. Similarly, Noble et al. [10] found that DRD2, examined either as the TaqI A allele or as a haplotype, was not associated with HA. These findings do not discount the possibility that these genes are at some stage involved in the development of this self-regulatory system, but rather suggest that their effect is moderated by other variables. For example, Enoch et al. [9] found that COMT was only associated with HA amongst female but not male subjects.

Within our samples, gender did not significantly effect behavioural inhibition scores – as found by Reuter et al. [1]. However, we found support for the finding that NS declines with age [23, 24], whereby individuals aged 18–29 years scored consistently higher than individuals 40+ years. Although, in the two-way and three-way interaction, age did not alter the significance of the gene loci effects.

Two evident sources of difference between our investigation and that of the original study are the personality measure used and the sample composition. Reuter et al. [1] found a significant association with two of the three BAS subscales. One of these scales 'fun seeking' correlates moderately with NS (r =.51, p <.001), whilst the other 'drive' does not [2]. Therefore, the BIS/BAS scales evaluate behavioural approach tendencies from a slightly different perspective to that of the TCI. Reuter et al. [1] examined healthy subjects, whilst all our participants had a current major depressive disorder. A genetic association may be more evident in a community sample which includes a range of behavioural approach and inhibition responses, whilst our samples of depressed patients may be heavily weighted for high HA [24, 25]. Also, as our sample is not primarily of German origin, it differs from Reuter et al.'s [1] with respect to ethnicity and therefore genetic heterogeneity may partly be responsible for the different results.

Variable findings may also reflect a lack of a direct effect of a polymorphism on the function of the gene product. For example, the functional effects associated with the DRD2 TaqI A polymorphism may be due to the polymorphism being located within the regulatory region of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene [26] or being in linkage disequilibrium with another DRD2 variant. This indistinctness may be further compounded by grouping A1A1 carriers with A1A2 carriers (due to the low frequency of the A1 allele) for analysis. Whether this is an accurate representation of the functionality of the polymorphism remains to be determined.

This study suggests that the association found by Reuter et al. [1] does not hold in a sample of depressed patients assessed using the TCI. Although, due to the interplay of metabolising enzymes and receptors it is expected that at some level these genetic factors are interdependent, yet how these facets might interact to influence personality remains unknown. Appraisal of both positive and negative results will hopefully provide some clues as to the contexts in which associations exist between genetic factors and specifically-defined behaviours.