The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits

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Abstract

Variations in personality traits are caused by interactions between multiple genes of small effect and environmental factors. To date, gender- and ethnicity-specific variations in personality have been established. In the present study, we aimed to test: 1) the effects of four polymorphisms of dopamine system genes: ANKK1/DRD2 Taq1A, DRD2 rs6275, SLC6A3 40-bp VNTR and rs27072, on personality traits; 2) whether these effects differ between men and women and between Russians and Tatars. A sample of 652 healthy individuals (222 men and 430 women) of Caucasian origin (233 Russians and 419 Tatars) from Russia was subjected to personality traits assessment with Eysenck Personality Inventory (EPI) and Temperament and Character Inventory-125 (TCI-125). The associations between each personality trait and polymorphisms were assessed with regression models adjusted for gender and ethnicity. There were significant effects of ANKK1/DRD2 Taq1A on Neuroticism (p = 0.016) and of SLC6A3 rs27072 on Persistence (p = 0.021) in both genders. The association between ANKK1/DRD2 Taq1A A2/A2-genotype and higher Novelty Seeking and lower Reward Dependence was shown in men only (p for gender interaction = 0.018). In women only, there was a significant association between SLC6A3 10R*G-haplotype and higher Persistence (p = 0.002). Our findings provide evidence for a modifying effect of gender on the associations between dopamine system genes and approach-related traits (in men) and Persistence (in women).

Research highlights

►ANKK1 gene-by-gender interaction effects on Novelty Seeking and Reward Dependence. ►Association of ANKK1 A1-allele with lower NS and higher RD was indicated in men only. ►Association of SLC6A3 10R*G-haplotype and higher Persistence in women.

Introduction

Personality traits are complex phenotypes affected by interactions of multiple genes of small effect with environmental factors. According to the psychobiological model, dopaminergic system represents the neurobiological basis for approach-related traits in general, and for Novelty Seeking (NS) in particular (Cloninger et al., 1993).

Dopamine D2 receptor gene (DRD2) (11q22-23) is a candidate for reward-related psychiatric disorders and personality traits. The most frequently examined single nucleotide polymorphism (SNP) is the Taq1A (rs1800497, or 32806C > T) (Grandy et al., 1989) located in the 3′-untranslated region of DRD2 (10 kB downstream of the last exon), and actually residing in a neighbouring ankyrin repeat and kinase domain containing 1 gene (ANKK1) and causing an amino acid substitution within the 11th ankyrin repeat of the ANKK1 (Glu713Lys), which might affect substrate-binding specificity of the gene product (Neville et al., 2004). Taq1A is a marker of functional differences of both DRD2 (Zhang et al., 2007) and ANKK1 (Hoenicka et al., 2010). For instance, diminished D2 receptor binding has been reported for Taq1A minor A1-allele in the majority of studies (Jönsson et al., 1999, Noble et al., 1991, Pohjalainen et al., 1998a, Ritchie and Noble, 2003, Thompson et al., 1997). Recently, the group of authors suggested a potential relationship of ANKK1 gene with the dopaminergic system based on the upregulation of ANKK1 mRNA level in mouse astrocyte cultures by apomorphine (Hoenicka et al., 2010). In addition, it has been hypothesized that the ANKK1 gene can be probably involved in the dopaminergic reward pathway through signal transduction (or other cellular response) (Neville et al., 2004), since genes of related function are sometimes found clustered together.

According to molecular-genetic studies, Taq1A A1-allele carriers have more tendencies for “reward-related psychiatric disorders”, including alcohol, opioid and nicotine addiction (Hietala et al., 1997, Ishiguro et al., 1998, Noble, 2003), pathologic gambling (Comings et al., 1996), hyperactive and impulsive symptoms (Rowe et al., 1999) and compulsive smoking habits (Hamajima et al., 2002). Moreover, the associations between A1-allele and higher NS (or sensation seeking) (Berman et al., 2002, Lin et al., 2007), higher Dependence (RD4 subscale of RD) (Lee et al., 2003), and increased reward responsiveness (Lee et al., 2007) have been reported. Synonymous substitution 939C > T (His313His) (rs6275) in exon 6 of DRD2 gene could be functional: for instance, the presence of G or C nucleotides in the last nucleotide in the codon could result in an increased gene expression (Sarkar et al., 1991). Molecular-genetic studies involving DRD2 rs6275 demonstrated an association of N1-allele (C-allele) or N1/N1-genotype (C/C) with alcoholism (Chen et al., 1997), migraine with aura, depression, anxiety (Peroutka et al., 1998), and schizophrenia (Monakhov et al., 2008).

Dopamine transporter gene (SLC6A3) (5p15.3) plays a critical role in the regulation of dopaminergic transmission by mediating active reuptake of dopamine from the synapse into the presynaptic terminal (Giros and Caron, 1993). It has been shown that the putamen dopamine transporter density correlated with detached personality and social desirability scores (Laakso et al., 2000). The 40 bp (base pairs) variable number of tandem repeats (VNTR) in the 3′ untranslated region of SLC6A3 gene (SLC6A3 VNTR) was shown to be functional, however increased gene expression was controversially associated either with 10-repeat allele (Fuke et al., 2001, VanNess et al., 2005) or 9-repeat allele (Miller and Madras, 2002). Several studies related dopamine transporter gene 9-repeat allele to severe alcohol withdrawal and alcohol dependence (Köhnke et al., 2005, Samochowiec et al., 2006). The rs27072 (2319G > A), located in 3′-UTR of SLC6A3, has been associated with ADHD (Feng et al., 2005, Galili-Weisstub et al., 2005, Laurin et al., 2007), bipolar disorder (Greenwood et al., 2006) and smoking (Ling et al., 2004). To date there have been no studies of this polymorphism in personality traits. Despite of the absence of data indicating the functional significance of rs27072 polymorphism located in 3′-UTR of SLC6A3 gene, there is some evidence pointing to the fact that sequence variation in the 3′-UTR of the gene could influence transcription, sub-cellular localization of mRNA, translation regulation, and/or maintenance of mRNA stability (Mignone et al., 2002).

Multiple studies indicated that gender could affect dopaminergic neurotransmission caused by hormonal and social influences on the individual during various phases of development (Costa et al., 2000). Thus, females were shown to have lower D2 receptor affinity for dopamine in human studies (Pohjalainen et al., 1998b) and dopamine D2 autoreceptor downregulation caused by estrogens was demonstrated in animal studies (Becker, 1999). Differences in traditions, social norms, and religion, as well as differences in allele frequencies in populations might also affect the personality. Since, very little is known about the role of gender and ethnicity as modifiers of association between dopamine system genes and personality, we aim to test: 1) the effects of four polymorphisms of dopamine system genes: ANKK1/DRD2 TAq1A, DRD2 rs6275, SLC6A3 40-bp VNTR and rs27072, on personality traits in different models; and 2) whether these effects differ between men and women. Since both of the studied subpopulations (Russians and Tatars) belong to Caucasians and possess, for instance, the small percent of East Eurasian mtDNA lineages (Khusnutdinova et al., 2007), the analysis was conducted in the total sample with ethnicity included as a covariate.

Section snippets

Subjects

In total, 652 healthy individuals, college students from Bashkortostan Republic of Russia without any individual or family (a first degree relative) history of psychopathologies based on self-reports, were enrolled. This sample consists of 222 men (mean age ± SD: 19.86 ± 2.44 years and age range: 17–25 years) and 430 women (mean age ± SD: 19.84 ± 2.41 years and age range: 16–25 years) of Caucasian origin (Russians (N = 214) or Tatars (N = 388)). Ethnicity was assessed based on self-reports of involved

Results

The distributions of genotype frequencies for all SNPs were consistent with Hardy–Weinberg equilibrium (P = 0.39 for DRD2/ANKK1 Taq1A, P = 0.96 for DRD2 rs6275, P = 0.71 for SLC6A3 rs27072, and P = 0.051 for SLC6A3 VNTR).

Personality scores for each genotype of the investigated polymorphisms (DRD2/ANKK1 Taq1A, DRD2 rs6275, SLC6A3 rs27072 and SLC6A3 VNTR polymorphisms) in the total sample, and in men and women separately are presented in Table 1. ANOVA conducted in the total sample and in gender-specific

Discussion

The present study of ANKK1/DRD2 and SLC6A3 genes in personality traits in healthy individuals was based on the results of personality traits measurement with two different inventories: Eysenck Personality Inventory (EPI) and Temperament and Character Inventory (TCI-125). The rationale for the inclusion of both inventories in the study was to test if not only the traits defined by TCI-125 (proposed to be influenced by neurotransmitter systems functioning (Cloninger et al., 1993)), but also

Conclusions

The present results provide useful information for the interpretation of genetic studies exploring the role of ANKK1/DRD2 and SLC6A3 gene polymorphisms in personality traits in healthy individuals. Future psychogenetic investigations of personality should seek to replicate and extend the present research, perhaps by examining more thoroughly the role of demographic and also environmental variables on gene–personality relationships.

The following are the supplementary materials related to this

Acknowledgements

This work was supported by the grant of Russian Foundation for Humanities (09-06-95601a/E and 08-06-591a) and by 7th Framework Programme ADAMS HEALTH-2009-4.3.3-1 grant no. 02.527.11.0006/3.

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