Scientific Correspondence

Molecular Psychiatry (2003) 8, 371–372. doi:10.1038/sj.mp.4001253

Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants

A Strobel1, K P Lesch2, S Jatzke2, F Paetzold1 and B Brocke1

  1. 1Institute of Psychology II, Dresden University of Technology, Dresden, Germany
  2. 2Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

Correspondence: A Strobel, E-mail: alexander.strobel@mailbox.tu-dresden.de

Sir – The initial findings of an association between the dopamine D4 receptor (DRD4) gene exon III polymorphism and the personality trait Novelty Seeking1,2 prompted a large number of follow-up studies.3 Nevertheless, there is still conflicting evidence whether the presence of the DRD4 exon III 7-repeat allele is associated with higher scores in Novelty Seeking. For example, our group confirmed this association in an earlier work,4 but we did not observe an association between DRD4 exon III and Novelty Seeking in a recent study,5 although both samples were drawn from the same population.

Since the expression of a behavioral phenotype is influenced by the developmental and physiologic effect of multiple gene variants, Benjamin et al6 suggested 'that failure to replicate associations between personality factors and some genes may be partially due to the presence of additional modifying common polymorphisms' (Benjamin et al,6 p 98). This view is based on their finding that in the absence of the short (s) allele of the serotonin transporter gene promoter-linked polymorphic region (5-HTTLPR)7 and in the presence of the val/val genotype of the catechol O-methyltransferase gene (COMT) val/met polymorphism,8 Novelty Seeking scores are higher in the presence of the DRD4 exon III 7-repeat allele.6

In order to examine, whether our failure to replicate the proposed association in our recent study 5 may, in part, be accounted for by the action of other genetic variants not included in the initial analyses, we followed the methodology of Benjamin et al6 and also genotyped our sample for 5-HTTLPR and the COMT val/met polymorphism. For analysis of gene–gene interaction, all three genotypes were available from 280 unrelated healthy volunteers of German ethnicity (212 women and 68 men; mean age: 21.9plusminus3.9 years, age range: 18–41 years). Novelty Seeking was assessed with the German version of the Tridimensional Personality Questionnaire,9 and individual genotypes were determined as previously described for DRD4 exon III,1 5-HTTLPR,7 and COMT.8 Table 1 gives the Novelty Seeking raw means and standard deviations for groups defined by COMT val/val vs. val/met vs. met/met genotype, 5-HTTLPR l/l vs l/s & s/s genotype, and absence (7-) vs presence (7+) of the DRD4 exon III 7-repeat allele. Based on the findings by Benjamin and associates,6 we hypothesized that in the group defined by 5-HTTLPR l/l genotype and the COMT val/val genotype, individuals with the DRD4 exon III 7-repeat allele would have higher Novelty Seeking scores than those without the 7-repeat allele.


To test this hypothesis, participants with the 5-HTTLPR l/l genotype and the COMT val/val genotype were selected, and Novelty Seeking scores of individuals with (n=10) and without the DRD4 exon III 7-repeat allele (n=17) were compared by means of one-way univariate analysis of variance. Age and gender were entered as covariates to control for possible stratification. There was a significant effect of DRD4 exon III on Novelty Seeking (F [1,23]=5.02, P=0.035; see Table 1). Individuals with the 7-repeat allele had higher Novelty Seeking scores (estimated marginal meanplusminusSEM: 18.35plusminus1.64) than individuals without the 7-repeat allele (13.68plusminus1.24).

Furthermore, following Benjamin et al,6 who observed significant interactions between 5-HTTLPR and DRD4 exon III, and between 5-HTTLPR and COMT, respectively, we performed a three-way univariate analysis of variance with the three polymorphisms as independent variables and with Novelty Seeking as dependent variable. Again, age and gender were entered as covariates. There were no significant main effects and interaction effects except for a significant main effect of DRD4 exon III (F [1,266]=4.98, P=0.026).

In summary, the present report describes an investigation whether failures to replicate the proposed association between DRD4 exon III and Novelty Seeking are in part due to the action of additional modulating genetic variants. Our results clearly support the hypothesis that in the presence of the long 5-HTTLPR allele and in the presence of the COMT val/val genotype, Novelty Seeking scores are higher in carriers of the DRD4 exon III 7-repeat allele.

Moreover, the present study revealed a DRD4 exon III main effect on Novelty Seeking when 5-HTTLPR and COMT are considered as additional factors in the analysis of variance. This finding is particularly intriguing in the light of our previous report of a lack of association between DRD4 exon III and Novelty Seeking in this sample, when DRD4 exon III is the only factor in the analysis.5 Although there are no interaction effects between the three polymorphisms in the present analysis, the additional 5-HTTLPR and COMT factors apparently modulated the effect of DRD4 exon III on Novelty Seeking in that they captured portions of error variance in the DRD4 exon III factor. Of course, our results should be interpreted with caution due to limitations in sample size, and therefore, further replication in larger samples is needed. Nevertheless, our findings underscore the notion that inclusion of additional genetic variations may help to resolve some of the inconsistencies in human gene-personality/behavior correlation studies.

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