Functional effects of a tandem duplication polymorphism in the 5′flanking region of the DRD4 gene

D’Souza, Ursula M.; Russ, Carsten; Tahir, Eda; Mill, Jonathan; McGuffin, Peter; Asherson, Philip; Craig, Ian W.

doi:10.1016/j.biopsych.2004.08.008

Cited by 107 publications

(75 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Three genomic regions have now been shown with various degrees of certainty to participate in the regulation of DRD4 receptor synthesis: the promoter 120 bp tandem duplication, 109 the C-521T promoter SNP 46 and the exon III VNTR. [110][111][112][113] One avenue of future research would be to examine all three loci in a single haplotype for their joint effect on expression.…”

Section: Drd4 Haplotypesmentioning

confidence: 99%

See 1 more Smart Citation

The molecular genetic architecture of human personality: beyond self-report questionnaires

2006

View full text Add to dashboard Cite

Molecular genetic studies of personality began with two high impact papers in 1996 that showed provisional associations between the dopamine DRD4 exon III repeat region and Novelty Seeking/Extraversion. These first two reports were shortly followed by an investigation linking Neuroticism/Harm Avoidance with the serotonin transporter (SLC6A4) promoter region polymorphism (5-HTTLPR). In the ensuing decade, thousands of subjects have been studied for association between these genes and personality, assessed by using self-report questionnaires, with erratic success in replication of the first findings for Novelty Seeking (DRD4) and Harm Avoidance (5-HTTLPR). Small effect sizes characteristic of non-Mendelian traits, polygenic patterns of inheritance and true heterogeneity between studies confound attempts to reach a consensus regarding the role of common polymorphisms in contributing to personality domains. Nevertheless, the current state of personality genetics is far from being bleak. Several new paradigms especially functional neuroimaging or 'imaging genomics' have strengthened the connection between 5-HTTLPR and anxiety-related personality traits. The demonstrations that early environmental information can considerably strengthen and even uncover associations between genes and behavior (Caspi's seminal studies and more recently the demonstration that early environment impacts on DRD4 and Novelty Seeking) are notable and herald a new era of personality genetics. Finally, consideration of the broader phenotypic expression of common polymorphisms (e.g. the 'social brain', altruism, etc.) and the use of new experimental paradigms including neurophysiological, neuropsychological and computer games that go beyond the narrow self-report questionnaire design will enable a deeper understanding of how common genetic polymorphisms modulate human behavior. Human personality, defined by Webster as the quality or state of being a person or the complex of characteristics that distinguishes an individual, surely requires a more encompassing view towards understanding its complex molecular genetic architecture.

show abstract

Section: Drd4 Haplotypesmentioning

confidence: 99%

“…This polymorphism has been associated with attention deficit [105][106][107] and also with TPQ Novelty Seeking. 108 Subsequently, the longer allele (240 bp) was shown to display lower transcriptional activity than the short allele (120 bp) 108,109 and homozygous subjects for the short allele scored higher on TPQ Novelty Seeking.…”

mentioning

confidence: 97%

The molecular genetic architecture of human personality: beyond self-report questionnaires

2006

View full text Add to dashboard Cite

show abstract

“…Имеются важные данные о функцио-нальности полиморфизма DRD4120bp, располо-женного близко к промоторной области гена и, как показали [16], существенно влияющего на специ-фичную экспрессию гена DRD4. Возможно, имеет значение и сниженная транскрипционная актив-ность L-аллеля [17], что может нарушать функцио-нирование систем долговременной регуляции ре-цепторной активности и, как результат, изменять постсинаптический ответ на ДА. Пресинаптическая регуляция ДА нейромедиации также может быть из-менена влиянием Т-аллеля по локусу NcO гена до-фаминового рецептора типа 2, который, возможно, имеет влияние на регуляцию экспрессии гена.…”

Section: Discussionunclassified

Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach

Krupitsky

Кибитов

Blokhina

et al. 2015

Z. nevrol. psikhiatr. im. S.S. Korsakova

View full text Add to dashboard Cite

“…Several predicted transcription consensus binding sites lie within this duplication suggesting it may play a role in transcriptional activity of the gene [Seaman et al, 1999] and there is evidence for enhanced Sp1 binding capacity of the duplicated form [Ronai et al, 2004a]. Using luciferase reporter vectors and human cell lines, including SK-N-MC (human neuroepithelioma cells) and SH-SY5Y (neuroblastoma cells) [D'Souza et al, 2004], IMR32 cells (neuroblastoma) and Y79 cells (retinoblastoma) [Kereszturi et al, 2007], the 2-repeat has been shown to have reduced transcriptional activity compared to the 1-repeat. Kereszturi et al [2007] also tested a 4-repeat (480 bp) duplication which they had identified in their ADHD sample.…”

Section: Neuropsychiatric Geneticsmentioning

confidence: 99%

The DRD4 receptor Exon 3 VNTR and 5′ SNP variants and mRNA expression in human post‐mortem brain tissue

Simpson¹,

Vetuz²,

Wilson³

et al. 2010

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Genetic variation within the dopamine D4 receptor (DRD4) gene has been implicated in many neuropsychiatric disorders and behavioral traits. This variation includes the extensively studied exon 3 variably numbered tandem repeat (VNTR), and several 5' polymorphisms including a120-bp duplication and two single-nucleotide polymorphisms at -521 C/T (rs1800955) and -616 C/G (rs747302). Several reports have provided evidence for a functional role for some of these variants using in vitro techniques. This study investigated the functionality of these polymorphisms in 28 human post-mortem brain tissue samples by quantifying DRD4 mRNA expression in relation to genotype. No statistically significant relationship between genotype and mRNA expression levels was found for these four polymorphisms although a weak trend toward the 7-repeat of the exon 3 VNTR reducing DRD4 mRNA expression was found. Employing post-mortem brain tissue, rather than using in vitro techniques may provide a more relevant paradigm to study functional effects of reported risk alleles.

show abstract

Functional effects of a tandem duplication polymorphism in the 5′flanking region of the DRD4 gene

Cited by 107 publications

References 58 publications

The molecular genetic architecture of human personality: beyond self-report questionnaires

The molecular genetic architecture of human personality: beyond self-report questionnaires

Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach

The DRD4 receptor Exon 3 VNTR and 5′ SNP variants and mRNA expression in human post‐mortem brain tissue

Contact Info

Product

Resources

About