Genetic polymorphisms in the human dopamine D4 receptor (DRD4) gene, especially the
exon 3 variable number of tandem repeats (VNTR), have been related to several psychiatric
disorders and personality traits. A homologous exon 3 VNTR has been described in dogs,
and we previously showed an association between the DRD4 exon 3 polymorphism and activity/impulsivity
trait in German shepherds. In this study, we present a detailed analysis of the intron
2 VNTR of the DRD4 gene. A short and a long form of the intronic variation were identified
in 678 unrelated dogs from five breeds and in 22 wolves. For molecular analysis, the
intron 2 region was cloned into a promoterless luciferase reporter vector that led
to an elevation in transcriptional activity. Moreover, an allelic difference in promoter
activity was detected, and a repressive effect of the long allele was observed. Behavioral
analysis of 96 unrelated German shepherds showed a significant association between
the social impulsivity endophenotype of the Greeting Test and both the exonic (P =
0.002) and the intronic (P = 0.003) VNTRs of the DRD4 gene. Moreover, an additive
effect of the two polymorphisms was also shown (Spearman's rho = 0.356, P = 0.0004).
In conclusion, these results give further support to our previous findings that the
DRD4 gene is associated with dog behavior. We also present molecular evidence for
the functional role of the intron 2 VNTR in the canine DRD4 gene.
