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

Abstract

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...

The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study

“…Using the reported z-scores, it is also possible to calculate the effect sizes between the groups (in SD units; d), where d = 0.2 is a small effect size, d = 0.5 is a medium effect size, and d = 0.8 is a Figure 1 Worldwide allele frequencies for the DRD4 exon three VNTR polymorphism. 13,15,[20][21][22]24,[72][73][74][75][76] large effect size. 58 The personality variables were normally distributed.…”

Dopamine D4 receptor polymorphism modulates cue-elicited heroin craving in Chinese

“…Later, however, Li et al (2000) didn't replicate the previous result with a larger sample. Furthermore, a study with German samples failed to find an association between long allele and opioid dependence either (Franke et al 2000).…”

Association analysis of the DRD4 and COMT genes in methamphetamine abuse

“…An excess of the 7-repeat variant of the DRD4 exon III VNTR has been associated with novelty seeking [Ebstein et al, 1996], opiate-dependence [Kotler et al, 1997], alcohol craving [Hutchison et al, 2002], and substance abuse [Vandenbergh et al, 2000]. However, other studies have failed to replicate these associations [Franke et al, 2000;Li et al, 2000].A recent study we carried out showed weak association between the 7-repeat allele of the DRD4 exon III VNTR and methamphetamine abuse in a Chinese population [Chen et al, 2004]. Methamphetamine is a potent psychostimulant with a high dependence on liability and consumption is linked to acute and chronic psychological disturbance, including psychosis.…”