Neuropsychopharmacologia Hungarica

2007. március, IX. évfolyam 1. szám [translated version]

Eredeti közlemény

A dopamin D4-es receptor génvariánsok vizsgálata figyelemhiányos hiperaktivitási zavarban

Kereszturi Éva1, Király Orsolya1, Csapó Zsolt1, Tárnok Zsanett2, Gádoros Júlia2, Sasvári-Székely Mária1és Nemoda Zsófia1
1 Semmelweis Egyetem, Orvosi Vegytani, Molekuláris Biológiai és Pathobiokémiai Intézet, Budapest
2 Vadaskert Gyermekpszichiátriai Kórház és Szakambulancia, Budapest

 

Original paper

Analysis of the dopamine D4 receptor gene variants in attention deficit hyperactivity disorder

Eva Kereszturi1, Orsolya Kiraly1, Zsolt Csapo1, Zsanett Tarnok2, Julia Gadoros2, Maria Sasvari-Szekely1and Zsofia Nemoda1
1 Semmelweis Egyetem, Orvosi Vegytani, Molekuláris Biológiai és Pathobiokémiai Intézet, Budapest, Hungary
2 Vadaskert Gyermekpszichiátriai Kórház és Szakambulancia, Budapest, Hungary

The human dopamine D4 receptor (DRD4) gene has been extensively studied as a candidate gene for attention deficit hyperactivity disorder (ADHD). Both the 5' regulatory region and the coding sequence contain a number of polymorphisms. The most widely investigated polymorphism of the DRD4 gene is the 48 bp VNTR (Variable Number of Tandem Repeats) in the third exon. The promoter variants have received particular attention in the past few years due to their possible role in the regulation of gene expression. In this study we describe an association analysis of the 120 bp duplication and three sequence variations (SNPs, Single Nucleotide Polymorphism; -616 C/G, -615 A/G, -521 C/T) in the 5' region of the DRD4 gene is presented among children with ADHD. In case-control approach, the 1-repeat form of the 120 bp duplication had a significantly higher frequency among ADHD children than controls, both in allele-(p=0.047), and genotype (p=0.019) distributions. There was no significant difference between the ADHD and control groups in the allele or genotype frequencies of the investigated SNPs. The transcriptional effect of the 120 bp duplication was analysed in luciferase reporter system. The different 120 bp duplication alleles (1-repeat, 2-repeat and the newly identified 4-repeat allele) was found to have an effect on transcriptional activity of the DRD4 gene in both neuroblastoma and retinoblastoma cell lines in a dose-dependent manner. The higher was the repeat number of the 120 bp sequence in the promoter, the stronger was the decrease of the gene transcription (1-repeat > 2-repeat > 4-repeat; p<0.01). These results of association and functional analyses suggest that the 1-repeat form of the 120 bp duplication might be a risk factor of ADHD.

Keywords: dopamine D4 receptor (DRD4), attention deficit hyperactivity disorder (ADHD), polymorphism, association-analysis