Novel polymorphisms in the upstream region of the human dopamine D4 receptor (DRD4) gene

We found nine novel polymorphisms in the upstream region of the human dopamine D4 receptor (DRD4) gene of Japanese by direct sequencing. These polymorphisms are −809G > A, −768G > A, −616C > G, −603T > del, −602G > del, −600G > C, −376C > T, −291C > T, and −128G > T. One known polymorphism, −521C > T, was also recognized. Six of these sites were identified as restriction fragment length polymorphisms (RFLPs). Received: June 11, 1999 / Accepted: June 23, 1999     

Association between dopamine D4 receptor (DRD4) exon III polymorphism and Neuroticism in the Japanese population

The association between the dopamine D4 receptor (DRD4) exon III polymorphism and personality trait of novelty seeking (NS) has been studied intensively. In the Japanese population, the results of the previous studies did not always coincide. In the present study, we investigated the association between the polymorphism and personality traits evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) in 196 Japanese subjects. A meta-analysis of the present and previous Japanese studies was also conducted regarding NS. As a result, significant association was observed between the polymorphism and personality traits evaluated by using NEO PI-R as a whole (p=0.022, MANCOVA). Subsequent analyses showed a significant association between short alleles (2-4 repeats) and higher scores for Neuroticism or its subscales, Anxiety, Depression, and Vulnerability (p=0.015, 0.039, 0.021, and 0.008, respectively, uncorrected). No other significant difference in the scores for NEO PI-R was observed in the subsequent analyses. Significant association was also observed between the polymorphism and scores for STAI as a whole (p=0.004, MANCOVA). Subsequent analyses did not show significant association, although a weak trend for the relation between the genotype consisting of short alleles and Trait Anxiety was observed (p=0.10, uncorrected). The meta-analysis showed no significant association between the polymorphism and NS. Thus, the present study suggested the association between the short allele of the DRD4 exon III polymorphism and personality trait of Neuroticism in Japanese subjects.     

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

A –521CT polymorphism in the promoter of the dopamine receptor D4 gene (DRD4) has been associated with novelty-seeking behavior in Japanese. Given that the dopaminergic system might also play an important role in bone metabolism, the relation of the –521CT polymorphism of DRD4 to bone mineral density (BMD) was examined in 2,228 Japanese subjects (1,123 men; 1,105 women) who were randomly recruited to a population-based, prospective cohort study. BMD at the radius was measured by peripheral quantitative computed tomography, and that for the total body, lumbar spine, right femoral neck, right trochanter, and right Wards triangle was measured by dual-energy X-ray absorptiometry. Genotype was determined with a fluorescence-based allele-specific DNA primer assay system. For men, BMD for the distal radius, total body, lumbar spine, trochanter, or Wards triangle was lower in individuals with the CC genotype than in the combined group of TT and TC genotypes or in those with the TT genotype or with the TC genotype. The urinary concentration of deoxypyridinoline was slightly, but significantly, greater in men with the CC genotype than in those with the TT or TC genotypes or with the TT genotype. For women, there were no differences in BMD among –521CT genotypes. These results implicate DRD4 as a candidate locus for reduced BMD in Japanese men.     

Association analysis of polymorphisms in the prepronociceptin gene and schizophrenia

The human prepronociceptin (ppNoc) gene is located on chromosome 8p21, and several linkage studies have suggested that the susceptibility locus for schizophrenia is present in this chromosomal region. We investigated genetic variations in the promoter and coding regions of the ppNoc gene to determine if there may be an association between naturally occurring mutations and the manifestation of schizophrenia. Association analyses for the variations found were conducted between 87 unrelated schizophrenic patients and 100 healthy controls. Polymorphisms were found at both the −503 locus (G/A) in the promoter region and the 353 locus (Ala118Gly) in exon 3. Additionally, rare variants were identified at the −261 locus (A/G) in the promoter region, the 515 locus (Gln172Arg) in exon 3, and the 561 locus (G/A) in the untranslated region of exon 3. A significant difference was observed in allele frequency at the 353 locus between controls and patients with continuous-course schizophrenia (P = 0.0237), and between patients with and without prominent negative symptoms (P = 0.0201). However, neither difference was significant after Bonferroni correction. In addition, there were no significant differences in genotype and allele frequencies at either the −503 or 353 locus between the control group and patients with schizophrenia. These results suggest that ppNoc gene polymorphisms have no association with schizophrenia. Received: March 7, 2001 / Accepted: April 21, 2001     

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.     

Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.     

Association study between the dopamine D4 receptor gene and schizophrenia

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic cloza-pine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)_n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed. © 1995 Wiley-Liss, Inc.     

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.     

Lack of imprinting of the human dopamine D4 receptor (DRD4) gene

The term genomic imprinting has been used to refer to the differential expression of genetic material depending on whether it has come from the male or female parent. In humans, the chromosomal region 11p15.5 has been shown to contain 2 imprinted genes (H19 and IGF2). The gene for the dopamine D4 receptor (DRD4), which is of great interest for research into neuropsychiatric disorders and psychopharmacology, is also located in this area. In the present study, we have examined the imprinting status of the DRD4 gene in brain tissue of an epileptic patient who was heterozygous for a 12 bp repeat polymorphism in exon 1 of the DRD4 gene. We show that both alleles are expressed in equivalent amounts. We therefore conclude that the DRD4 gene is not imprinted in the human brain. © 1996 Wiley-Liss, Inc.     

Association of DRD4 and COMT polymorphisms with anger and forgiveness traits in healthy volunteers

Although the biological basis of trait anger, anger expression, and forgiveness are not well understood, there has been growing evidence that anger-related dispositions are heritable and associated with genetic polymorphisms. The purpose of the present study was to investigate the possible relationship between anger and forgiveness traits and the dopamine receptor D4 (DRD4) and catechol-O-methyltransferase (COMT) Val158 Met polymorphisms in healthy Korean subjects. Three hundred and thirty-five healthy college students were recruited, and the 308 participants with a complete data set (184 males, 124 females) were included in the data analysis. DNA of the subjects was isolated from whole blood cells, and DRD4 variable number of tandem repeats and COMT Val158 Met polymorphisms were genotyped using polymerase chain reaction. Participants performed the State-Trait Anger Expression Inventory and Trait Forgivingness Scale measuring anger and forgiveness traits. The DRD4 2-repeat (2R) allele group had significantly lower anger in tendency and higher forgiveness traits than the 4R allele group in males. Our results provide evidence that the 2R allele of DRD4 in a Korean sample might have a different function from the 4R allele and a gender-specific role on anger-related traits. The COMT Val158 Met polymorphism had no significant relationship with anger and forgiveness traits. These findings suggest a possible relationship between anger expression styles and forgiveness traits and dopaminergic dysfunction.     

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.     

多巴胺D2受体基因与精神分裂症和双相情感障碍关联研究的荟萃分析

遗传因素是精神分裂症(schizophrenia,SCZ)和双相情感障碍(bipolar disorder,BP)的重要致病因素,已有大量基因关联研究表明多巴胺D2受体基因与两种精神疾病可能存在风险关系,然而许多研究的结果并不一致.系统的荟萃分析可以弥补单个研究样本量小可能引起的结果偏差.经过严格筛选,本文纳入8个关于BP和49个关于SCZ的独立研究,荟萃分析多巴胺D2受体3个基因多态性(141C Del/Ins、TaqI-A、SCr311Cys)与这两种精神疾病的风险关系.结果 提示Ser311Cys的G/C多态性和SCZ发病显著关联,而TaqI-A的T/C多态性和BP发病存在显著关联(P<0.05).基因型分析结果揭示了多巴胺D2受体基因Ser311Cys携带G等位基因的基因型是SCZ的风险因素,TaqI-A的TT基因型可能是BP的风险因子而对于SCZ是保护因子.     

Homozygosity at the dopamine D3 receptor gene in schizophrenic patients

Dopamine receptors have long been implicated in the etiology of schizophrenia. It has been reported an association of schizophrenia with homozygosity at the dopamine D3 receptor gene locus. We have investigated the distribution of a D3 receptor gene polymorphism (BalI) in 107 schizophrenic Spanish patients and 100 healthy matched controls. No statistically significant differences between the patients and control group were detected with respect to either allele frequencies or genotype distribution. However, if not corrected for multiple testing, a correlation was found between homozygosity and early age of schizophrenia (χ² = 3.1, df = 1, P = 0.03) and between A1 allele frequency and disorganized and undifferentiated schizophrenia (χ² = 3.4, df = 1, P = 0.03; χ² = 2.7, df = 1, P = 0.05, respectively). These results suggest the possibility that D3 polymorphisms may be among the physiological factors underlying schizophrenia; though not the determining factor.     

多巴胺D3受体基因Ser-9-Gly多态性精神分裂症的关联研究

为探讨精神分裂症与多巴胺 D3受体基因 ( dopamine D3receptor gene,DRD3) Ser-9-Gly多态性是否关联。应用PCR-RFLP方法检测了广州地区汉族人群中 1 2 3例家族史阴性、1 1 3例家族史阳性精神分裂症患者、1 6 8例家族史阴性患者父母和 4 7例正常老年人中多巴胺 D3受体基因 Ser-9-Gly多态性 ,并对多巴胺 D3受体基因各等位基因及基因型与精神分裂症进行了相关分析 ,DRD3与精神分裂症、患者性别及家族史均无关联 ( P>0 .0 5 )。提示广州地区汉族人群中DRD3基因 Ser-9-Gly多态性与精神分裂症没有关联。     

Association between novelty seeking and dopamine receptor D4 (DRD4) exon III polymorphism in Japanese subjects

In this study, we investigated the association between dopamine receptor D4 (DRD4) exon III polymorphism and novelty seeking in 69 Japanese women. The group of subjects with long allele (≥5 repeats) exhibited significantly elevated novelty seeking scores in comparison with subjects lacking the long allele. By contrast, the scores for harm avoidance, reward dependence, and persistence were statistically indistinguishable in the two group of subjects. With regard to the subscales of novelty seeking, the scores for exploratory excitability and extravagance were significantly higher in subjects with the long allele than in subjects lacking the long allele. However, no significant associations with impulsiveness or disorderliness were recognized. Our results suggest that although long alleles of the polymorphic exon III repeats are low in the Japanese population, there is an association between long alleles of DRD4 exon III polymorphism and novelty seeking. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:469–471, 1999. © 1999 Wiley-Liss, Inc.     

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.     

Association of intron 1 variants of the dopamine transporter gene with schizophrenia

The dopamine transporter (DAT1) gene has been implicated in the pathogenesis of many neuropsychiatric disorders, including schizophrenia. The present study aimed to investigate association of the DAT1 gene polymorphisms with schizophrenia in a Han Chinese population. Two single nucleotide polymorphisms (SNPs) in the DAT1 gene (rs2975223 and rs2455391) were tested in 368 patients with schizophrenia and 420 healthy controls, of whom 293 patients underwent an assessment of psychotic symptoms through the positive and negative syndrome scale (PANSS). The chi-square test (χ²) showed disease association for rs2455391 (corrected p = 0.023 for allelic association and p = 0.034 for genotypic association, respectively). The rs2975223(G)–rs2455391(C) haplotype was associated with increased risk of the illness (p = 0.0012, OR = 2.09, 95% CI = 1.28–3.42). Quantitative trait analysis showed that rs2455391 was associated with positive symptoms, general symptoms and global symptoms but not with negative symptoms. The present results suggest that the DAT1 gene may be mainly involved in the development of the positive symptoms in the Chinese population.     

Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients

We have examined the hypothesis that a variable number of tandem repeats in the third cytoplasmic loop of the dopamine D4 receptor influences clinical response to clozapine using a sample of 189 schizophrenic patients. Alleles of the 48-bp repeat, which range from two to ten copies in the normal human population, were analysed by the polymerase chain reaction using genomic DNA as template. Association between these alleles and response to clozapine was tested using the difference in pre-and post-treatment GAS scores as a measure of response. We found no statistically significant variation between genotypic groups and response by analysis of variance. We conclude that the variation of the number of 48-bp repeats alone does not determine response to clozapine. Larger studies are underway to determine if there is a more subtle relationship with sequence variation within the repeats or at other polymorphic sites within the gene that may provide evidence for a component of clozapine's action being at D4 receptors. © 1995 Wiley-Liss, Inc.     

Affect-modulated startle reflex and dopamine D4 receptor gene variation

The affect-modulated acoustic startle response (ASR) might be a promising indicator for emotional reactivity as an endophenotype (an intermediate level between genetics and phenotypes), which we expected to be associated with the DRD4 polymorphism. Therefore, the affect-modulated ASR was examined in 114 healthy volunteers, 74 lacking the DRD4 7R allele (7R-absent group) and 41 with at least one DRD4 7R allele (7R group). Results revealed the well-known affect–modulated ASR in the 7R-absent group. The 7R group, however, was characterized by a blunted affect-modulated ASR, especially by a reduced startle potentiation toward unpleasant pictures. Associations between the exploratory assessed 5-HTT, COMT, and DAT polymorphisms and affect-modulated ASR were not found. Results speak for the importance of the DRD4 polymorphism in modulating emotional responses and also for the usefulness of the affect-modulated ASR as an endophenotype.