Norepinephrine transporter and alpha(2c) adrenoceptor allelic variants and personality factors

It has been suggested that reward dependence, as measured by the Tridimensional Personality Questionnaire (TPQ), is related to central noradrenergic activity, a proposition supported by two studies of urinary norepinephrine metabolite. In the current investigation, 190 normal young Han Chinese were examined, with genetic polymorphisms determined for the norepinephrine transporter (1287G/A) and the alpha(2c)-adrenoceptor (Del322-325) to test the association with TPQ personality traits. No significant association was demonstrated for these two polymorphisms and any of the TPQ personality-factor scores, including reward dependence and its subscales. Our negative findings suggest that the investigated polymorphisms of the norepinephrine transporter and the alpha(2c) adrenoceptor do not play a major role in the reward-dependence personality trait as assessed by TPQ.     

Allelic variants of the alpha1a adrenoceptor and the promoter region of the alpha2a adrenoceptor and temperament factors.

Human personality traits are partially determined by genes. It has been suggested that the reward-dependence dimension assessed by the Tridimensional Personality Questionnaire (TPQ) is related to the central noradrenergic system. Our population-based association study tested the hypothesis that genetic variants of the adrenoceptor are associated with this personality trait. The alpha1a- and the alpha2a-adrenoceptor genotypes were determined for 198 healthy Han Chinese who had completed the TPQ. We found no significant differences for TPQ personality-factor scores, including reward dependence and its subscales, for subjects showing different adrenoceptor genotypes. Our negative findings suggest that polymorphisms of the alpha1a adrenoceptor and of the promoter region of the alpha2a-adrenoceptor have no major effect on the reward-dependence personality trait as assessed by TPQ.     

5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: Interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms

We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT_2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT_2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT_2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT_2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT_2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT_2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort. Am. J. Med. Genet. 74:65–72, 1997. © 1997 Wiley-Liss, Inc.     

Allelic variants of dopamine receptor D4 (DRD4) and serotonin receptor 5HT2c (HTR2c) and temperament factors: replication tests

The contribution of genetic factors to personality differences between individuals is evidenced by twin and adoption studies. Ebstein et al. [1996, 1997a, 1997b] reported an association between the long repeat allele of the dopamine D4-exon-III receptor polymorphism and the human personality dimension novelty seeking (NS), between the 5HT2c-ser-23 allele and reward dependence, and an interaction between both receptor polymorphisms and reward dependence. Subsequent replication tests mainly reported controversial results for the association between DRD4-exon-III long repeat and NS. We examined a homogeneous study population of 190 healthy male students of middle European descent, aged between 20 and 30 years using Cloninger's TPQ in order to replicate Ebstein's findings. Using a significance level of 1%, no association between the long repeat of the DRD4-exon-III polymorphism and NS and between the 5HT2c receptor polymorphism and reward dependence was found, but a significant interaction effect of DRD4 and 5HT2c receptor polymorphisms on reward dependence was observed in accordance to Ebstein's report.     

Serotonin transporter genetic polymorphisms and harm avoidance in the Chinese

The association for the harm avoidance (HA) dimension, as assessed by the Tridimensional Personality Questionnaire (TPQ), and the serotonin-transporter genetic polymorphisms has been investigated with controversial results. The aim of the present study was to replicate this investigation and to establish the association for a Chinese population. Two polymorphisms of the serotonin transporter (5HTT-LPR, serotonin transporter-linked polymorphism region; 5HTT-VNTR, variable number tandem repeat polymorphism in intron 2 of the serotonin transporter gene) were determined for 192 healthy Han Chinese who had completed the TPQ. No significant differences were demonstrated for TPQ HA scores, including the sub-scales, for subjects with different 5HTT-LPR genotypes. A significantly higher HA2 sub-score was demonstrated for subjects carrying the 10-12 5HTT-VNTR genotype, however, compared with those from the 12-12 genotype group, for the male population (P = 0.007). Our findings suggest that the 5HTT genetic polymorphism may be associated with HA scores; however, the effect is influenced by ethnicity and gender.     

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:430–436, 1999. © 1999 Wiley-Liss, Inc.     

Lack of a strong association between HLA class II,tumour necrosis factor and transporter associated with antigen processing gene polymorphisms and virological response to α‐interferon treatment in patients with chronic hepatitis C

The aim of the study was to investigate whether polymorphisms of the HLA class II, tumour necrosis factor (TNF) and transporter associated with antigen processing (TAP) genes influence the response to α‐interferon in patients with chronic hepatitis C. Twenty‐seven sustained responders and 55 non‐responders to α‐interferon monotherapy were investigated. HLA‐DRB1, DQA1, DQB1, TNFA, TNFB, TAP1 and TAP2 alleles were determined by PCR‐based molecular techniques. Sustained virological response was defined as undetectable serum hepatitis C virus (HCV) RNA for at least 3 years after the end of treatment. Probability (P) values were corrected for the number of alleles tested (P_c). Viral genotype 1b was more frequent in responders than in non‐responders (56% vs. 26%, P = 0.009). HLA‐DQB1*02 occurred less frequently in responders than in non‐responders (14.8% vs. 29%, P_c not significant). HLA‐DRB1*11 and DQB1*0602 were found in 22.2% and 9.3% of responders and in 10.9% and 1.8% of non‐responders, respectively (P_c not significant). There was no difference in the distribution of TNF alleles in the two groups. Twenty‐four (88.8%) responder patients as compared with 34 (61.8%) non‐responders were TAP1*0101 homozygous (P_c not significant). Thus, in European Caucasoids with chronic hepatitis C, we could not demonstrate a strong association between HLA class II, TNF, and TAP gene polymorphisms and response to interferon treatment.     

Lack of association between polymorphisms of the dopamine receptor D4 and dopamine transporter genes and personality traits in a Korean population

Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.     

D2 and D4 dopamine receptor polymorphisms and personality

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D₂ dopamine receptor (DRD2) and D₄ dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1,B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:257–267, 1998. © 1998 Wiley-Liss, Inc.     

Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population

It is well established that approximately 50% of the variance in personality traits is genetic. The goal of this study was to investigate a relationship between personality traits and the T-182C polymorphism in the norepinephrine transporter gene. The participants included 115 healthy adults with no history of psychiatric disorders and other physical illness during the past 6 months. All participants were tested with the Temperament and Character Inventory and genotyped norepinephrine transporter gene polymorphism. Differences on the Temperament and Character Inventory dimensions among three groups were examined with one-way analysis of variance. Our study suggests that the norepinephrine transporter T-182C gene polymorphism is associated with reward dependence in Koreans, but the small number of study participants and their sex and age heterogeneity limits generalization of our results. Further studies are necessary with a larger number of homogeneous participants to confirm whether the norepinephrine transporter gene is related to personality traits.     

Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits

The human dopamine D4 receptor (DRD4) is of major interest in molecular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (−768G>A in the negative modulator region; −521C>T, −376C>T, and −291C>T in the cell type-specific promoter region; and −616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The −768G>A polymorphism was significantly associated with reward dependence (P = 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene. Received: August 28, 2000 / Accepted: October 25, 2000     

Allelic association analysis of the dopamine D2, D3, 5‐HT2A,and GABAAγ2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA_Aγ2, and the serotonin transporter (5‐HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter ? 141ΔC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter ? 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5‐HTT gene, and one polymorphism (G3145A) in GABA_Aγ2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism ? 141ΔC (genotype‐wise and allele‐wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the ? 141ΔC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype‐wise, P = 0.006, allele‐wise, P = 0.016) but not for injectors of heroin (genotype‐wise, P = 0.81, allele‐wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5‐HTT, DRD3 and GABA_Aγ2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter ? 141ΔC polymorphism. © 2002 Wiley‐Liss, Inc.     

Deletion of the α2A/α2C‐adrenoceptors accelerates cutaneous wound healing in mice

The α2‐adrenoceptors regulate the sympathetic nervous system, controlling presynaptic catecholamine release. However, the role of the α2‐adrenoceptors in cutaneous wound healing is poorly understood. Mice lacking both the α2A/α2C‐adrenoceptors were used to evaluate the participation of the α2‐adrenoceptor during cutaneous wound healing. A full‐thickness excisional lesion was performed on the dorsal skin of the α2A/α2C‐adrenoceptor knockout and wild‐type mice. Seven or fourteen days later, the animals were euthanized and the lesions were formalin‐fixed and paraffin‐embedded or frozen. Murine skin fibroblasts were also isolated from α2A/α2C‐adrenoceptor knockout and wild‐type mice, and fibroblast activity was evaluated. The in vivo study demonstrated that α2A/α2C‐adrenoceptor depletion accelerated wound contraction and re‐epithelialization. A reduction in the number of neutrophils and macrophages was observed in the α2A/α2C‐adrenoceptor knockout mice compared with wild‐type mice. In addition, α2A/α2C‐adrenoceptor depletion enhanced the levels of nitrite and hydroxyproline, and the protein expression of transforming growth factor‐β and vascular endothelial growth factor. Furthermore, α2A/α2C‐adrenoceptor depletion accelerated blood vessel formation and myofibroblast differentiation. The in vitro study demonstrated that skin fibroblasts isolated from α2A/α2C‐adrenoceptor knockout mice exhibited enhanced cell migration, α‐smooth muscle actin _protein expression and collagen deposition compared with wild‐type skin fibroblasts. In conclusion, α2A/α2C‐adrenoceptor deletion accelerates cutaneous wound healing in mice.     

Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence

Genetic research on cocaine dependence (CD) may help clarify our understanding of the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D₂ (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3′ variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, we hypothesize that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n = 347) and unaffected controls (n = 257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. We observed no statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms. Our study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD.     

Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits.

Anxiety-related personality traits, such as NEO neuroticism and TCI/TPQ harm avoidance, have been shown to have significant genetic components. To date, however, no specific genetic variants that contribute to these traits have been conclusively identified. At least 26 studies have investigated a putative association between a functional serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. The results of these studies have been inconsistent with some studies finding evidence for an association, and others not. We performed a meta-analysis of all applicable studies investigating this association. In the overall analysis (N = 5,629 subjects), we found suggestive evidence for an association between the 5-HTTLPR short allele (s) and increased anxiety-related personality trait scores (P = 0.087). However, we also found strong evidence for heterogeneity. This heterogeneity is largely explained by substantial variation between the studies in the inventory used. When the analysis was stratified by inventory type, there was a significant association between 5-HTTLPR and NEO neuroticism (P = 0.000016), a non-significant association between 5-HTTLPR and TCI/TPQ harm avoidance (P = 0.166), and no association between 5-HTTLPR and other anxiety-related personality traits (P = 0.944). There was no evidence that these results were either due to publication bias or accounted for by any one single study. We conclude that there is a strong association between the serotonin transporter promoter variant and neuroticism as measured in the NEO personality inventory and that non-replications are largely due to small sample size and the use of different inventories.     

No association between serotonin transporter gene polymorphisms and personality traits.

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.     

Association of TAP1 and TAP2 genes with susceptibility to pulmonary tuberculosis in Koreans

Tuberculosis remains an important public health problem in Koreans. However, very few studies have reported on the genetic factors associated with TB susceptibility in Koreans. The aim of this study was to elucidate the genetic factors associated with susceptibility to pulmonary tuberculosis (PTB). We investigated the transporter associated with antigen processing –1 (TAP1) and TAP2 gene polymorphisms in 160 Korean PTB patients (categorized according to extent of lesion and TB medication history) and 210 controls. TAP2*C/E frequency was significantly increased in the PTB (p_c = 0.004, OR = 2.28). TAP2*Bky2/C/E were enriched in the retreated, far‐advanced and total PTB compared with the controls (p_c = 0.015, OR = 3.27; p_c = 0.019, OR = 2.56; p_c = 2.8 × 10^?4, OR = 2.42, respectively). In the comparison of TAP2 gene with the DRB1*08:03, which is associated with TAP2*Bky2 and PTB in Koreans, we demonstrated the hierarchy of these association factors. TAP2*C/E is independent factors as strong as DRB1*08:03, and TAP2*C/E interacts with DRB1*08:03, resulting in a striking combined association. Our results suggest that TAP2 gene has an association with PTB susceptibility, the extent of the lesion or recurrence. These associations are independent from and additive with DRB1*08:03.     

Characterological traits of recovered patients with panic disorder and agoraphobia.

Three self-rating personality inventories were administered to 33 patients who had recovered from panic disorder associated with agoraphobia and to 33 healthy subjects matched for sociodemographic variables. The personality inventories comprised the Tridimensional Personality Questionnaire (TPQ), which provides three major dimensions (novelty seeking, harm avoidance and reward dependence), the Anxiety Sensitivity Index (ASI) and the Emotional Inhibition Scale (EIS). Agoraphobic patients reported significantly more TPQ harm avoidance and anxiety sensitivity than controls. Although these findings might have been influenced by residual anxiety symptoms in panic-free patients and could also apply to patients with other anxiety disorders, they suggest that harm avoidance and anxiety sensitivity may be risk factors for developing agoraphobia and panic disorder. There may be overlap between this characterologic cluster and prodromal symptoms of panic disorder with agoraphobia, such as anxiety, phobias and hypochondriasis.     

Cross‐cultural traits for personality of patients with Parkinson's disease in Japan

Recent studies suggest that Parkinson's disease (PD) is associated with particular personality traits. Using Cloningers's Tridimensional Personality Questionnaire (TPQ), Menza and colleagues [1993: Neurology 43:505–508] reported a possible association between PD and a reduced score in the novelty seeking (NS) dimension of the TPQ. We sought to determine whether this association, which was found in a study conducted in the United States, could also be found among Japanese PD patients. We performed personality assessments of 67 Japanese PD patients, using the TPQ test. The results suggest that Japanese PD patients have significantly lower scores in the NS dimension of the TPQ, as well as significantly higher harm avoidance (HA) scores, compared with matched control subjects. Furthermore, the PD patients undergoing treatment for depression using antidepressant drugs scored significantly higher in the HA dimension than PD patients who did not receive antidepressant drug treatment. Our results suggest that the high HA score, and the low NS score in the TPQ test observed in patients with PD, is a cross‐cultural phenomenon, although the influence of depression, long‐term treatment, and premorbid gene/environmental interactions may also affect these personality traits. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:1–3, 2000. © 2000 Wiley‐Liss, Inc.     

The -181 A/C polymorphism in the excitatory amino acid transporter-2 gene promoter affects the personality trait of reward dependence in healthy subjects

There have been some animal and human data suggesting that excitatory amino acid transporter (EAAT)-2, the major subtype of EAAT, is involved in human mental function and behavior. Recently, it has been shown that the -181 A/C polymorphism in the EAAT2 gene promoter affects plasma glutamate concentrations in humans. In the present study, the association of this genetic polymorphism with personality traits was examined in 575 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory, and the EAAT2 polymorphism was detected by a PCR-RFLP method. The scores of reward dependence were significantly (p=0.017) lower in the group with the A allele (A/A and A/C) than in that without this allele (C/C). When males and females were analyzed separately, the significant difference between the two genotype groups was observed in females (p=0.021) but not in males. The present study thus suggests that the -181 A/C polymorphism in the EAAT2 gene promoter affects the personality trait of reward dependence in healthy subjects.