Since the observation of an association between the dopamine D4 receptor (DRD4) exon III polymorphism and the temperament trait of Novelty Seeking, 1 replication studies have yielded both positive 2-5 and negative 6-12 results. This raised the question whether the initial findings must be regarded as false positives. 13 However, demographic or methodological differences between studies may have obscured the small effect of the DRD4 polymorphism on Novelty Seeking. 14 Examination of clinical or older cohorts may have led to an underestimation of possible associations due to a restricted variation of Novelty Seeking in these cohorts. The use of different questionnaires provides another source of variation. In order to replicate the initial findings as precisely as possible, a cohort of 136 healthy, young volunteers was genotyped, and Novelty Seeking was ascertained using the TPQ. 15,16 In addition, further aspects of novelty seeking behavior have been ascertained through additional trait measures. We could observe the reported association between long DRD4 alleles and significantly elevated scores (age-and sexresidualized) on the TPQ-Novelty Seeking total scale as well as on two of the subscales, Exploratory Excitability and Extravagance. The results provide further confirmation for the role of the DRD4 exon III polymorphism in modulation of Novelty Seeking. In addition, the pattern of associations between the polymorphism and other scales suggests that this polymorphism has its effect on exploratory, extravagant, and extraverted, rather than on impulsive and monotony-avoidant subtypes of Novelty Seeking.DRD4 exon III allele frequencies in our cohort were comparable to those observed in other populations. The two most common alleles were the 4 and the 7 repeat, the two most common genotypes were 4,4 and 4,7. Thus, absence vs presence of the 7 repeat allele, and the 4,4 vs 4,7 genotype, respectively, were chosen as independent variables in the one-way analyses of variance.We could observe the reported association between DRD4 exon III allele length and Novelty Seeking (Tables 1 and 2). The presence of the 7 repeat was associated with significantly elevated Novelty Seeking total scores (F 1,134 = 11.54, P = 0.001). The effect had a size of 0.6 standard deviation units and accounted for 8% of the variance. Among Novelty Seeking subscales, the presence of the 7 repeat was associated with elevated scores on NS1 (Exploratory Excitability; F 1,134 = 4.97, P = 0.027), NS2 (Impulsiveness; F 1,134 = 4.60, P = 0.034), and NS3 (Extravagance; F 1,134 = 19.06, P = 0.00003). Similar, and even stronger, associations could be observed when comparing subjects with the 4,4 vs 4,7 genotype (Table 2). However, only the associations between the 7 repeat and NS total and NS3, and between the 4,7 genotype and NS, NS1, and NS3 remained significant after correction for multiple testing (␣ = 0.0016; see Methods and Materials).As effects of demographic variables can confound the results of association studies, we carried out analyses of vari...
