A Genetic Polymorphism in the Promoter Region of DRD4 Associated with Expression and Schizophrenia

Okuyama, Yuki; Ishiguro, Hiroki; Toru, Michio; Arinami, Tadao

doi:10.1006/bbrc.1999.0630

Biochemical and Biophysical Research Communications

1999

DOI: 10.1006/bbrc.1999.0630

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A Genetic Polymorphism in the Promoter Region of DRD4 Associated with Expression and Schizophrenia

Yuki Okuyama

Hiroki Ishiguro

Michio Toru

et al.

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Cited by 152 publications

(160 citation statements)

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“…The present findings are consistent with such a hyperactivity and suggest that this may be modulated by BDV infection possibly through interference of viral components with neurotransmitters (eg, glutamate and aspartate). 4 Future studies should validate these findings and further investigate possible mechanisms of this neurotropic virus in relation to altered cortical activity in psychiatric disorders. …”

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confidence: 89%

“…3 More recently, the focus of attention has thus shifted towards DRD4 markers located in the gene's promoter region, on account of their relevance to gene expression. 4,5 In particular, two variants are currently being regarded as modulators of DRD4 expression; namely, a 120 bp promoter length polymorphism (refSNP-ID rs4646984), and a À521T4C marker (refSNP-ID rs1800955) mapped to the gene's core promoter, 6 which was also implicated in the modulation of Extraversion in African Americans. 7 The present investigation was designed to test these polymorphisms as possible genetic determinants of personality traits in a larger population of healthy subjects.…”

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confidence: 99%

“…The DRD4 promoter markers were assessed using PCR-based protocols previously described, 4,5 and were confirmed to be in Hardy-Weinberg equilibrium. Allele and genotype frequencies were in close agreement with results from previous studies in Caucasians (f S ¼ 0.21 for allele grouping, see below; f T ¼ 0.54).…”

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confidence: 99%

“…8 Alterations in cortical arousal, in turn, correspond to the cluster of approach traits, that is, Extraversion, Novelty Seeking and Sensation Seeking, in most models of biological substrates of personality. 9 It follows that genetic traits which reduce Extraversion, and demonstrably affect DRD4 gene expression in cellbased assays, 4 are highly likely to shape individual variability in approach behaviours. An additional interest in the gene's promoter region has arisen from a large body of 46 association studies addressing the personality of healthy subjects.…”

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confidence: 99%

“…2 Second, the gene encoding ACAT1 (SOAT1) is located near a chromosomal region (1q25) that full genome screens suggest may harbor a novel AD gene. 3,4 We present here the results of a comprehensive genetic assessment of SOAT1 (including all three variants previously analyzed) 1 in the NIMH AD Genetics Initiative Study sample. 4,5 Marginally significant findings were also assessed in a smaller, independent sample of sibships discordant for AD, the 'Consortium on AD Genetics' (CAG) Study sample.…”

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Variation at the DRD4 promoter modulates extraversion in Caucasians

et al. 2005

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between OCD patients and controls (RT: 537739 vs 528750 ms; HR: 98.671 vs 98.272%), respectively. Neural generators of the N1 were estimated with the LORETA method, indicating a major source in the left temporoparietal region (Brodmann areas (BA) 19/37/39, Figure 1b) and a weaker mirror image source on the right. Comparing individual source solutions statistically (voxel-wise), group H and the control group differed in the medial frontal (BA 23/24) and lateral temporo-occipital (BA 19) cortex (Figure 1c). This is the first demonstration that BDV activity (amount of BDV-CICs) is associated with diseaserelevant and attention-related cognitive changes (increased N1) in humans, in particular in secondary visual areas and the anterior cingulate gyrus. The increased N1 amplitude in group H patients may be explained by defective thalamic filter mechanisms, given a proposed modulation by thalamic input to the cortex. 10 Indeed, functional neuroimaging studies 9 strongly suggest that OCD involves hyperactivity of striato-thalamo-cortical networks. The present findings are consistent with such a hyperactivity and suggest that this may be modulated by BDV infection possibly through interference of viral components with neurotransmitters (eg, glutamate and aspartate). 4 Future studies should validate these findings and further investigate possible mechanisms of this neurotropic virus in relation to altered cortical activity in psychiatric disorders.

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confidence: 89%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Variation at the DRD4 promoter modulates extraversion in Caucasians

et al. 2005

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Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects

Zhu

Liu

et al. 2000

Am. J. Med. Genet.

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Heroin abuse is a major social and public health problem in many parts of the world, yet relatively little is known about its etiology. Although genes play a role in determining susceptibility, they are expected to be of small effect with considerable heterogeneity. Because the dopamine system is involved in reward, its neurotransmitter receptors are candidates for etiological involvement in addiction. In the present study, we examine two polymorphisms in the dopamine D4 receptor, a VNTR in exon III and a point mutation in the promoter (-512C/T) that affects transcriptional efficiency. We examined a sample of 405 heroin-abusing subjects and 304 controls from Sichuan Province, Southwest China. One hundred twenty-one of these cases and 154 controls were previously used in a study of the DRD4 VNTR [Li et al., 1997], and the remainder are newly ascertained. The two polymorphisms were in weak but detectable linkage disequilibrium (1, 418 chromosomes, P < 0.00001, D' = 0.17). When we compared the heroin-abuse group with controls, we found no significant difference between the patients and controls for either polymorphism in the DRD4 gene or their haplotypes. We were also unable to replicate our earlier association between "long" DRD4 alleles and heroin abuse. However, division of the sample by route of administration (nasal inhalers or injectors) produced a significant difference between inhalers and controls for the DRD4 VNTR (six-fold corrected P = 0. 018 by allele) but not for injectors of heroin. The association we observed between inhalers and the DRD4 polymorphism is difficult to interpret, although it is possible that the association is explained by different levels of novelty seeking between the two subgroups.

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5?-Untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder

et al. 2001

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Recently the molecular genetic basis of attention-deficit hyperactivity disorder (ADHD) has been the focus of a number of studies with the majority of these investigating the role of dopamine system genes. A great deal of attention has been focused on the possible involvement of the dopamine D4 receptor gene (DRD4) following a report of an association of ADHD with the allele containing seven copies of the 48-bp repeat in the third exon. In this paper we extended the search for the molecular explanation for the observed association by testing three polymorphisms in the region 5' to the dopamine receptor D4 gene transcription start site for linkage to ADHD. We specifically targeted polymorphisms in the region 5' to the start site of transcription as DNA variants in this region could alter the transcription level of the gene and hence the phenotype. We did not observe significant evidence for biased transmission of any of the alleles at these three polymorphisms to ADHD probands using the transmission disequilibrium test. We conclude that these three polymorphisms are not related to the ADHD phenotype.

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A Genetic Polymorphism in the Promoter Region of DRD4 Associated with Expression and Schizophrenia

Cited by 152 publications

References 33 publications

Variation at the DRD4 promoter modulates extraversion in Caucasians

Variation at the DRD4 promoter modulates extraversion in Caucasians

Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects

5?-Untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder

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