Association between Novelty Seeking and the −521 C/T polymorphism in the promoter region of the DRD4 gene

Abstract

Association between the human personality trait 'Novelty Seeking' and the polymorphism of the DRD4 gene was first reported by Ebstein 1 and Benjamin 2 in 1996. This was soon followed by replication studies in various ethnic groups and by studying the role of other neurotransmitter receptor and transporter genes in the genetic determination of human temperament. More recently, several polymorphic sites of the upstream regulatory region of the DRD4 gene have been described.3 Among these the −521 C/T single nucleotide polymorphism (SNP) was shown to be associated with the Novelty Seeking (NS) scores of the Temperament and Character Inventory (TCI) in a Japanese male population. 4 We have investigated the −521 C/T SNP polymorphism in a Caucasian (Hungarian) population, 5 and here we report a replication of the Japanese findings, in an association study involving 109 healthy Hungarian volunteers. We found a weak association between NS and CC vs CT or TT genotypes (P Ͻ 0.06). Examination of this relation in male and female sex groups, however, strengthened the association for females (P Ͻ 0.01), but showed no genotypic effect for males. Molecular Psychiatry (2001) 6, 35-38. Human temperament, as measured by various selfreport questionnaires including TPQ (or a new version known as TCI) 6 and NEO-PI-R, 7 was shown to have considerable inherited components.8 Novelty Seeking (NS) is one of the four dimensions in the psychobiological model of temperament, which are thought to be independently heritable, and manifested from an early age. 9 The NS scale was designed to measure exploratory, impulsive and extravagant behavior, and has been related to the dopamine system by Cloninger. Searching for association between common genetic polymorphisms and specific personality traits, recent studies have concentrated on distinct candidate genes. First, the variable number of 48-bp repeats (VNTR) in the third exon of the human dopamine D4 receptor gene (DRD4) was shown to be correlated with the personality trait of Novelty Seeking, as measured by the TPQ 1 or the NEO-PI-R, 2 although the replications of the initial findings have been controversial. [10][11][12][13] Further studies concerning the regulatory region of the genes encoding receptors and transporters involved in neurotransmission revealed associations between a novel polymorphism of the DRD4 promoter region and NS in Japanese subjects. 4 This polymorphism is a CϾT substitution in a CpG island at one end of a cell-type specific regulatory element, between −591 and −123 bp relative to the first nucleotide of the DRD4 gene.14 Using a transient expression system, the −521 T allele was shown to be approximately 40% less active than the −521 C variant in a human retinoblastoma cell line, 4,15 suggesting the relevance of this polymorphism to the dopaminergic system. Moreover, a significantly higher frequency of the CC genotype was found among schizophrenic patients. 15Previously we have described the distribution of −521 C and −521 T alleles in a nonclinical Hungarian populati...

No association of the −521 C/T polymorphism in the promoter of DRD4 with novelty seeking

“…There was no statistically significant difference between the low and high scoring groups (P = 0.91). In contrast to the report by Ronai et al, 13 homo- Table 1 The number of observed −521C/T genotypes in the high and low novely seeking groups…”

“…In the case of the association described between a serotonin transporter gene polymorphism and a quantitative personality trait, neuroticism, it has been shown that the polymorphism may have an effect on trait values from the middle but not the extremes of its distribution. 18 Our study design cannot exclude a similar possibility, but we rather suggest that the association of NS with −521C/T observed by Okuyama et al 12 and Ronai et al 13 should be interpreted as a reflection of linkage disequilibrium between the studied polymorphism and the putative variant having a functional Molecular Psychiatry effect on NS scores. A dense set of polymorphisms in the DRD4 gene, its promoter as well as in other genes in the vicinity of the DRD4 gene must be studied, preferably in large, representative samples, to resolve this intriguing question.…”

“…These authors also found that the Tvariant of the polymorphism reduces transcriptional efficiency in vitro and thus, this polymorphism might be functional in vivo. Recently, Ronai et al 13 confirmed association with the promoter polymorphism and NS (P Ͻ 0.01) in 109 healthy university and high school students. Here we attempt to replicate this finding in a sample consisting of extreme NS scorers from a population-wide birth cohort in northern Finland.…”

“…The T-allele was more common than the C-allele (59% vs 41%), and allele frequencies were remarkably similar to the frequencies observed in the Japanese and Hungarian samples. 12,13 Both low and high scoring groups differed significantly from Hardy-Weinberg equilibrium (P = 0.005 and 0.001, respectively). This could imply non-random mating with respect to this locus or be an effect of the relatively recent settlement of this geographical region.…”

Association of a polymorphism of the dopamine receptor D4 gene with bone mineral density in Japanese men

“…Sequence variability within the dopamine receptor D4 gene (DRD4) has been implicated in the personality trait of novelty seeking, which is related to extroversion (Benjamin et al 1996;Ebstein et al 1996). A C-to-T single nucleotide polymorphism (SNP) at position -521 of DRD4 relative to the translation start site has been associated with novelty-seeking behavior in independent studies of Japanese (Okuyama et al 2000) and Hungarians (Ronai et al 2001). With the use of a transient expression system, Okuyama et al (2000) showed that the transcriptional activity of the -521T allele of DRD4 was reduced by $40% compared with that of the -521C allele in a human retinoblastoma cell line, suggesting functional relevance of this SNP in dopaminergic neurotransmission.…”