Dopamine is one of the neurotransmitters, which affect various mental functions and behaviors. Pharmacological research on schizophrenia has proposed the dopamine hypothesis, which states that symptoms of schizophrenia result from excessive dopaminergic activity [1]. Personality traits have also been considered to depend on the secretion and metabolism of dopamine [2]. Based on this concept, several molecular genetic studies have been conducted on personality traits with respect to dopamine-related genes. Particularly, the association between a 48 bp variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine D4 receptor (DRD4) gene and novelty seeking (NS) has been studied intensively ever since the first study conducted by Ebstein et al. [3]. However, a limited number of studies have investigated other dopamine receptor genes, such as dopamine D2 receptor (DRD2) and dopamine D3 receptor (DRD3) genes. The DRD4 structurally resembles the DRD2 and DRD3 and displays a pharmacological profile similar to that of the DRD2. In addition, the abundance of DRD4 is extremely low compared with DRD2 [4]. Therefore, the DRD2 and DRD3 genes could also be candidates for personality-related genes. In the present study, we investigated the DRD2, DRD3, and tyrosine hydroxylase (TH) genes, which is the rate-limiting enzyme involved in the synthesis of catecholamines, in relation to personality traits in Japanese subjects. In addition to the association of each gene, epistasis (gene-gene interaction) among the genes was also assessed.
In the field of neuroimaging, a relation between the density of the DRD2 and the personality trait of novelty seeking (NS) was indicated [5]. A significant correlation between DRD2 density in the brain and a detached personality was also observed by Farde et al. [6], which was replicated by Breier et al. [7]. In the molecular genetic study of personality traits, TaqI A polymorphism in the 3' region was the first focus of attention, although the polymorphism is not functional. The association between TaqI A1 allele and NS has been mainly investigated [8]. Several functional polymorphisms have been studied in the DRD2 gene. The Ser311Cys polymorphism is a missense mutation located in exon 7, the putative third cytoplasmic loop. The Cys allele was shown to be less effective than the Ser allele in inhibiting cAMP synthesis [9], indicating a functional deficit of the Cys allele. However, no association was observed between the polymorphism and personality traits in Gebhardt et al. [10]. To our knowledge, no other studies investigated the association between the Ser311Cys polymorphism and personality traits. The -141C Ins/Del polymorphism, located in the promoter region, was observed to affect luciferase activity in vitro [11]. The polymorphism was also observed to be in linkage disequilibrium with the functional C957T polymorphism [12]. Jonsson et al. [13] observed the association between the -141C Del variant and a detached personality, while Katsuragi et al. [14] did not observe any association between the polymorphism and personality traits in the Japanese subjects. The -241A/G polymorphism is not functional and has no effect on luciferase activity in vitro [11]. To our knowledge, no association study has been conducted between the polymorphism and personality traits.
With respect to the DRD3 gene, the Ser9Gly polymorphism was investigated in relevant to personality traits. Genotypes of this variant were observed to affect their dopamine binding affinity [15], indicating a possible functional effect. Czermak et al. [16] observed the association between DRD3 mRNA expression in peripheral blood lymphocytes and the personality trait of persistence. Staner et al. [17] observed the association between the polymorphism and NS in bipolar patients. While Ebstein et al. [18] observed a significant interaction among the DRD3, DRD4, and serotonin 2C receptor (5-HT2C) gene polymorphisms on reward dependence, no association was found between the polymorphism and personality traits in healthy subjects [19,20]. To our knowledge, no association study has been conducted between the DRD3 gene and personality traits in Japanese subjects.
Another candidate, TH is the rate-limiting enzyme involved in the synthesis of catecholamines; it converts tyrosine to dihydroxyphenylalanine (DOPA). A (TCAT)n repeat polymorphism in the first intron, which was suggested to have a relationship with catecholamine turnover rates [21], was investigated in relation to personality traits [22]. A tendency for high score for Neuroticism was observed in carriers of T8 allele, and high score for Conscientiousness and low score for Openness in women with T6/T10 genotype. No other polymorphism within this gene was investigated, including Val81Met in exon 3 [23] or PstI site in exon 10 [24], in relation to personality traits. Thus, further investigation will be needed to clarify the relationships between the DRD2, DRD3, and TH genes and personality traits.
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