Abstract
What is already known about this subject
CYP2D6 mediates, to some extent, the synthesis of the neurotransmitters, serotonin and dopamine in the brain. A positive relationship between CYP2D6 activity and personality has been suggested, while other studies have failed to find a relationship.
Therefore, because of these inconsistent findings, the association between CYP2D6 polymorphism and interindividual variability in personality has not yet been resolved.
What this study adds
The detailed genotypes for CYP2D6 were identified using DNA tip in a large number of Japanese subjects. However there were no correlations between scores of personality and CYP2D6 genotypes.
This study demonstrated that there was no significant association between CYP2D6 activity and personality trait in the Japanese population.
Aims
The polymorphic enzyme CYP2D6 is expressed not only in liver but also in brain at low concentrations. CYP2D6 mediates, to some extent, the synthesis of the neurotransmitters, serotonin and dopamine. We investigated a possible association between the genetic polymorphism of CYP2D6 and individual personality trait.
Methods
Mentally and physically healthy volunteers were recruited (n = 342). Temperament and Character Inventory (TCI) and CYP2D6 genotyping were performed in all subjects. We detected mutated alleles which were identified using the Amplichip CYP450 DNA chip.
Results
The number of phenotypes, assumed by genotype for ultrarapid metabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM) and poor metabolizers (PM) were 4 (1.1%), 262 (76.6%), 75 (21.9%) and 1 (0.3%), respectively. There were no differences in scores for novelty seeking, harm avoidance, reward dependence or persistence among the CYP2D6 phenotypes. The number of mutated alleles for CYP2D6 did not differ for scores of novelty seeking, harm avoidance, reward dependence or persistence. In subitem analyses, only RD3 (attachment) had a significant difference both in the CYP2D6 phenotype (P< 0.05) and genotype (P< 0.05).
Conclusions
This study did not demonstrate a significant association between CYP2D6 activity and personality trait because of the small interindividual variability in CYP2D6 activity within the Japanese population.
Keywords: CYP2D6, genotype, Japanese, personality
Introduction
Cloninger et al.[1] demonstrated that human personality consists of seven dimensions including three temperament dimensions and four character dimensions, and on the basis of this model they developed the temperament and character inventory (TCI), a questionnaire for assessing personality traits. Of the temperament dimensions, which include novelty seeking, harm avoidance, reward dependence, and persistence, three have been assumed to be related to monoamine neurotransmitters, novelty seeking with dopaminergic activities, harm avoidance with serotonergic activities and reward dependence with noradrenergic activity.
It has been reported that CYP2D6 is expressed not only in the liver but also in the brain at low concentrations [2]. The CYP2D6 in the brain has been shown to interact with the dopamine transporter and it has been suggested that it plays a role in the catabolism and processing of neurotransmitters [3–5]. Genetic polymorphism in CYP2D6 has been associated with smoking behaviour and this modification may occur through the involvement of CYP2D6 in the dopaminergic pathway. In addition, CYP2D6 mediates the synthesis of the neurotransmitters, serotonin and dopamine, from tyramine and 5-methoxytryptamine [2]. Since these neurotransmitters are linked with personality trait according to Cloninger's model, it is likely that genetic polymorphism of CYP2D6 is associated with individual personality. However, the association is inconsistent. Several studies have suggested a positive relationship between CYP2D6 activity and personality [6–8], while another study failed to find the relationship [9].
Therefore, the aim of the present study was to clarify the possible relationship between genotypes of CYP2D6 polymorphism and behavioural traits in a large sample of Japanese, as measured by the TCI.
Methods
This study was approved by the Ethics Committee of Hirosaki University School of Medicine. The subjects enrolled consisted of Japanese students and medical staff within the medical school (n = 342, male = 166, female = 176). Their mean age was 29.9 ± 11.4 years (range 18–69 years). After giving the subjects a full description of the study, written informed consent to participate was obtained from each of them. The subjects were asked to complete the 240 items of the Japanese version of the TCI, whose reliability and validity had been established by Kijima et al.[10]. The 240 items were allocated into four factors of temperaments (novelty seeking, harm avoidance, reward dependence and persistence) and three factors of characters (self-directedness, co-operativeness and self-transcendence), where self-transcendence consisted of self-forgetfulness, transpersonal identification and spiritual acceptance. Genotyping of CYP2D6 was performed using the AmpliChip CYP450 test® DNA chip (Roche Co., Tokyo, Japan). The AmpliChip CYP450 Test provides materials for genotyping the CYP2D6 gene, encompassing 31 known mutations (CYP2D6*2, *3, *4, *5, *6, *7, *8, *9, *10AB, *11, *14, *15, *17, *18, *19, *20, *25, *26, *29, *30, *31, *35, *36, *40, *41, *1XN, *2XN, *4XN). The alleles which led to no enzyme activity are CYP2D6*3, *4, *5, *6, *7, *8, *11, *14, *15, *19, *20 and *40. The alleles which led to decreased enzyme activity are CYP2D6*9, *10, *17, *29, *36 and *41. CYP2D6*2 and *35 are regarded as normal enzyme activity. Based on the CYP2D6 genotypes, subjects were grouped into four main phenotypes: poor metabolizer (PM) (two deficit alleles, e.g. *5/*5), intermediate metabolizer (IM) (either two reduced activity alleles or one reduced activity allele and one no activity allele, e.g. *4/*10, *5/*10, *10/*10), extensive metabolizer (EM) (one or more wild type alleles, e.g. *1/*1, *1/*2, *1/*5, *1/*10), and ultrarapid metabolizer (UM) (more than two copies of wild type, e.g. *1/*1XN, *1/*2XN). The mean scores for the seven factors of the TCI were compared among UM, EM and IM and between the number of mutated alleles using anova. Because only one of our subjects was a PM, PM was excluded from the statistical analysis. The result was defined as being significant at P < 0.05.
Results
The genotypes of our subjects were *1/*1 (n = 65, 19.0%), 1/*2 (n = 33, 9.6%), *1/*4 (n = 1, 0.3%), *1/*5 (n = 95, 4.4%), *1/*10 (n = 95, 27.8%), *1/*14 (n = 5, 0.3%), *1/*36 (n = 1, 0.3%), *1/*41 (n = 5, 1.5%), *1/*1xN (n = 2, 0.6%), *1/*2xN (n = 1, 0.3%), *2/*2 (n = 7, 2.0%), *2/*4 (n = 1, 0.3%), *2/*5 (n = 6, 1.8%), *2/*10 (n = 30, 8.8%), *2/*14 (n = 1, 0.3%), *2/*41 (n = 1, 0.3%), *2/*2xN (n = 1, 0.3%), *4/*10 (n = 1, 0.3%), *5/*5 (n = 1, 0.3%)), *5/*10 (n = 19, 5.6%), *5/*36 (n = 1, 0.3%), *10/*10 (n = 50, 14.6%), *10/*14 (n = 1, 0.3%), *10/*41 (n = 31, 0.9%). The number of phenotypes, assumed by genotype, for UM, EM, IM and PM were 4 (1.1%), 262 (76.6%), 75 (21.9%) and 1 (0.3%), respectively. There were no differences in the mean scores for the seven TCI factors between the phenotypes, assumed by genotype (Table 1). In subitem analyses, only RD3 (Attachment) had a significant difference in CYP2D6 phenotype (P = 0.017).
Table 1.
Comparison of the temperament and character inventory (TCI) subitem scores among phenotypes assumed by CYP2D6 genotypes
| UM (n = 4) | EM (n = 262) | IM (n = 75) | PM (n = 1) | Significance | |
|---|---|---|---|---|---|
| Novelty seeking | 18.3 (16.7, 19.8) | 21.4 (20.9, 22.0) | 21.5 (20.4, 22.5) | 27 | NS |
| Harm avoidance | 19.3 (13.2, 25.3) | 19.8 (19.0, 20.6) | 20.0 (18.6, 21.2) | 17 | NS |
| Reward dependence | 17.5 (15.9, 19.1) | 14.7 (14.3, 15.1) | 15.5 (14.7, 16.2) | 15 | NS |
| Persistence | 4.8 (1.2, 8.3) | 4.4 (4.1, 4.6) | 4.2 (3.8, 4.6) | 7 | NS |
| Self-directedness | 32.0 (24.1, 40.0) | 26.1 (25.3, 26.9) | 26.8 (25.2, 28.4) | 27 | NS |
| Co-operativeness | 31.5 (27.3, 35.7) | 28.0 (27.4, 28.6) | 28.4 (27.2, 29.6) | 32 | NS |
| Self-transcendence | 7.8 (4.5, 11.0) | 10.7 (10.1, 11.3) | 9.6 (8.4, 10.7) | 13 | NS |
Data are mean (95% confidence interval); UM; ultra rapid metabolizer, EM, extensive metabolizer, IM; intermediate metabolizer, PM; poor metabolizer.
The number of CYP2D6 genotypes based on the number of mutated alleles was 109 (31.9%) for zero alleles, 157 (45.9%) for one allele, and 76 (22.2%) for two alleles, respectively. The number of mutated alleles for CYP2D6 did not differ with the scores of TCI for six factors except self-transcendence which differed significantly. (Table 2). Post hoc analysis showed a significant difference between 0 mutated allele vs. 1 mutated allele (P = 0.034). In subitem analyses, only RD3 (attachment) had significant difference in CYP2D6 genotype (P = 0.034).
Table 2.
Comparison of the temperament and character inventory (TCI) subitem scores among the number of mutated alleles for CYP2D6
| Number of mutated alleles | ||||
|---|---|---|---|---|
| 0 (n = 109) | 1 (n = 157) | 2 (n = 76) | Significance | |
| Novelty seeking | 21.2 (20.3, 22.1) | 21.6 (20.8, 22.3) | 21.5 (20.5, 22.6) | NS |
| Harm avoidance | 20.3 (19.1, 21.4) | 19.4 (18.5, 20.4) | 20.0 (18.7, 21.3) | NS |
| Reward dependence | 14.6 (13.9, 15.2) | 14.9 (14.4, 15.4) | 15.4 (14.7, 16.2) | NS |
| Persistence | 4.3 (3.9, 4.6) | 4.5 (4.2, 4.8) | 4.2 (3.8, 4.6) | NS |
| Self-directedness | 26.4 (25.2, 27.7) | 26.0 (25.0, 27.1) | 26.8 (25.2, 28.4) | NS |
| Co-operativeness | 27.8 (26.7, 28.8) | 28.2 (27.4, 29.0) | 28.5 (27.3, 29.7) | NS |
| Self-transcendence | 9.7 (8.9, 10.6) | 11.3 (10.5, 12.1) | 9.7 (8.6, 10.8) | P < 0.05 |
Data are mean (95% confidence interval).
Discussion
The results of this study showed that scores of TCI (novelty seeking, harm avoidance, reward dependence and persistence) were not different between CYP2D6 phenotypes, as assumed by CYP2D6 genotype in Japanese. There are three possibilities to explain these results. First, since we had only one PM in the present study, PM was not included in statistical analyses. In addition, four UMs were not enough to detect the difference. This is ascribable to a narrower variation of CYP2D6 activity than that in previous studies using Caucasians. Therefore, the relatively small difference in CYP2D6 activity in Japanese was not enough to detect differences in personality. Second, most of our subjects were medical students and medical staff. Although statistical analyses were not performed, it is possible that the characteristics of our subjects deviated and had small interindividual variability in personality trait. Last, although cross validation between the original TCI and its Japanese version was performed, there is a possibility that differences in religion or race between Caucasians and Asians may result in less sensitivity of detection, such that a cultural difference cannot be excluded.
Similar to our finding, there was no difference between EM and IM in Japanese subjects [18]. Only three genotypes of *10/*10 and *1/*1 and *1/*10 were identified in this study, although the frequency of mutations other than CYP2D6*10 which predominantly affects CYP2D6 activity is relatively high in Japanese, e.g. CYP2D6*5. Therefore, this negative association between CYP2D6 activity and personality traits in Japanese was first demonstrated by our detailed study.
In conclusion, the present study demonstrated no significant association between CYP2D6 activity and personality trait in Japanese subjects. A significant factor affecting this outcome is the extremely rare frequency of subjects with outlying activity, leading to low interindividual variability in CYP2D6 activity in Japanese subjects.
Acknowledgments
This study was supported by a grant from International Research Supports, the Research Fund from Hirosaki University School of Medicine and a grant from the Hirosaki Research Institute for Neurosciences.
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