Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene

Cichon, Sven; Mm, Nöthen; Catalano, Mariana; Bella, Daniela Di; Maier, Wolfgang; Lichtermann, Dirk; Minges, Jürgen; Albus, Margot; Borrmann, M.; Franzek, Ernst

doi:10.1097/00041444-199505030-00001

Cited by 44 publications

(27 citation statements)

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“…An Sma I polymorphism in the 5 Ј noncoding region of DRD4 has been reported with A1 allele frequency of 0.95 in Caucasians (Petronis et al 1994b), and 0.99 in Asians (Nakatome et al 1996). This seems to be the same as a C-T polymorphism at nucleotide -11 with allele frequency in Germans, where the allele frequency of the wild-type allele is 0.93 (Cichon et al 1995). A mononucleotide (G n ) repeat occurs in intron 1, with alleles representing from six to ten guanine nucleotides present at this site (Petronis et al 1994a).…”

Section: Additional Polymorphisms Of Drd4mentioning

confidence: 94%

Dopamine D4 Receptor Gene Novelty or Nonsense?

Paterson

Sunohara

Kennedy

1999

Neuropsychopharmacology

154

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Section: Additional Polymorphisms Of Drd4mentioning

confidence: 94%

Dopamine D4 Receptor Gene Novelty or Nonsense?

Paterson

Sunohara

Kennedy

1999

Neuropsychopharmacology

154

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“…18 Most of the presently known variations, such as the 48-bp VNTR in the third exon 19 or the 12-bp VNTR in the first exon, 20 affect the size of the receptor, but some SNPs have also been shown. 21,22 However, reports on the effects of these structural variations on the receptor functioning and on the normal and pathological personality traits are controversial. 13,23 Recently, further polymorphic genes have been shown to influence the effect of the long allele of the DRD4 gene on NS, such as the cathecol O-methyltransferase (COMT) gene and the serotonin transporter promoter region.…”

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confidence: 99%

Association between Novelty Seeking and the −521 C/T polymorphism in the promoter region of the DRD4 gene

et al. 2000

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Association between the human personality trait 'Novelty Seeking' and the polymorphism of the DRD4 gene was first reported by Ebstein 1 and Benjamin 2 in 1996. This was soon followed by replication studies in various ethnic groups and by studying the role of other neurotransmitter receptor and transporter genes in the genetic determination of human temperament. More recently, several polymorphic sites of the upstream regulatory region of the DRD4 gene have been described.3 Among these the −521 C/T single nucleotide polymorphism (SNP) was shown to be associated with the Novelty Seeking (NS) scores of the Temperament and Character Inventory (TCI) in a Japanese male population. 4 We have investigated the −521 C/T SNP polymorphism in a Caucasian (Hungarian) population, 5 and here we report a replication of the Japanese findings, in an association study involving 109 healthy Hungarian volunteers. We found a weak association between NS and CC vs CT or TT genotypes (P Ͻ 0.06). Examination of this relation in male and female sex groups, however, strengthened the association for females (P Ͻ 0.01), but showed no genotypic effect for males. Molecular Psychiatry (2001) 6, 35-38. Human temperament, as measured by various selfreport questionnaires including TPQ (or a new version known as TCI) 6 and NEO-PI-R, 7 was shown to have considerable inherited components.8 Novelty Seeking (NS) is one of the four dimensions in the psychobiological model of temperament, which are thought to be independently heritable, and manifested from an early age. 9 The NS scale was designed to measure exploratory, impulsive and extravagant behavior, and has been related to the dopamine system by Cloninger. Searching for association between common genetic polymorphisms and specific personality traits, recent studies have concentrated on distinct candidate genes. First, the variable number of 48-bp repeats (VNTR) in the third exon of the human dopamine D4 receptor gene (DRD4) was shown to be correlated with the personality trait of Novelty Seeking, as measured by the TPQ 1 or the NEO-PI-R, 2 although the replications of the initial findings have been controversial. [10][11][12][13] Further studies concerning the regulatory region of the genes encoding receptors and transporters involved in neurotransmission revealed associations between a novel polymorphism of the DRD4 promoter region and NS in Japanese subjects. 4 This polymorphism is a CϾT substitution in a CpG island at one end of a cell-type specific regulatory element, between −591 and −123 bp relative to the first nucleotide of the DRD4 gene.14 Using a transient expression system, the −521 T allele was shown to be approximately 40% less active than the −521 C variant in a human retinoblastoma cell line, 4,15 suggesting the relevance of this polymorphism to the dopaminergic system. Moreover, a significantly higher frequency of the CC genotype was found among schizophrenic patients. 15Previously we have described the distribution of −521 C and −521 T alleles in a nonclinical Hungarian populati...

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“…The coding region of the human DRD4 gene has been the subject of extensive mutation screening and no variant, which could account for the effect through linkage disequilibrium, has been identified to date. 14,[17][18][19][20][21] However, since the mutation screenings were performed in other than Israelian and Chinese populations it cannot be excluded that population-specific variants exist. It may also be possible that population-specific variation is present in regulatory regions of the gene, which still have to be defined at the molecular level.…”

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DRD4 exon III VNTR polymorphism—susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach

et al. 2000

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Dopaminergic abnormalities are implicated in the pathogenesis of substance abuse. 1 Recently, two reports have been published suggesting an association between opioid dependence and presence of long alleles of the dopamine D 4 receptor (DRD4) gene exon III VNTR. 2,3 We have attempted to replicate this finding using a two-tiered strategy employing independent case-control and family-based association samples. Our study was possibly the largest candidate gene association study to date on opioid dependence in a sample of 815 subjects, 396 of whom were patients. We found long alleles of the DRD4 exon III VNTR in similar frequency among 285 heroin addicts and 197 controls. Furthermore, no preferential transmission of long alleles to affected offspring was observed in a sample of 111 patients and their parents. Our results, therefore, do not support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for opioid dependence in man. Molecular Psychiatry (2000) 5, 101-104.Although social and cultural influences are clearly important, family, twin and adoption studies indicate that genes contribute significantly to substance abuse, 4-6 including addiction to alcohol, cocaine and opioids. In search for genetic factors of opioid dependence, two recent case-control association studies have implicated the DRD4 exon III VNTR in the development of disease. 2,3 The study by Kotler et al 2 investigated the exon III VNTR in 141 male opioid-dependent subjects and 110 male control subjects from Israel, and found a significant excess of the 7-repeat allele, with an odds ratio of 3.06 (95% CI 1.38-4.35). Li et al 3 studied a Chinese sample of 121 heroin-dependent subjects and 154 controls. While the 7-repeat allele is extremely rare in Chinese populations and was only observed in two patients, dividing the VNTR alleles into 'long' (5-7 repeats) and 'short' (2-4 repeats) alleles showed a significant excess of long alleles in the patient group, with an odds ratio of 2.30 (95% CI 1.07-4.93). These observations clearly suggest a causal contribution of genetic variation in the DRD4 to the development of opioid dependence. In the present study, we have attempted to replicate this finding by genotyping DNA samples from 285 heroin addicts and 197 controls. Since a major flaw of case-control association studies is the problem of undetected population stratification, we also applied a family-based association study design by genotyping an independent sample of 111 heroin addicts and their parents to examine preferential transmission of alleles to affected offspring.The distributions of genotype and allele frequencies of the DRD4 exon III VNTR in patients and controls are shown in Tables 1 and 2. There were no significant differences between patients and controls in the frequency of the 7-repeat allele ( 2 = 2.444; df = 1; P = 0.188) nor in any of the other alleles (Table 2). At least one 7-repeat allele was found in 35.1% of heroindependent subjects and 27.4% of controls ( 2 = 3.157; df = 1; P = 0.076). Moreover, pat...

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Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene

Cited by 44 publications

References 0 publications

Dopamine D4 Receptor Gene Novelty or Nonsense?

Dopamine D4 Receptor Gene Novelty or Nonsense?

Association between Novelty Seeking and the −521 C/T polymorphism in the promoter region of the DRD4 gene

DRD4 exon III VNTR polymorphism—susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach

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