Studies of the 48 bp repeat polymorphism of theDRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse

TLDR

Prior studies have linked the 7‑repeat allele of the DRD4 48‑bp polymorphism to novelty‑seeking traits and disorders such as ADHD, Tourette syndrome, pathological gambling, and substance abuse, though subsequent research has produced inconsistent results. The study aimed to replicate these associations by genotyping 737 controls and 707 index subjects across four behavioral disorder groups. Genotyping was performed on participants from control and index groups to assess allele frequencies of the DRD4 48‑bp repeat polymorphism. Chi‑square analysis showed no significant association for the 7 allele alone, but carriers of any 5–8 allele (including all 7 alleles) were significantly over‑represented in pathological gambling, ADHD, Tourette syndrome, and the combined index group, with heterozygosity further elevating risk in gamblers and the total cohort; additional genotype‑dependent effects on drug‑dependence severity and other quantitative traits highlighted a complex, allele‑range–dependent role of DRD4 beyond the 7‑allele hypothesis.

Abstract

Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine whether we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, TS, and ADHD. Chi-square analysis of those carrying the 7 allele versus non-7 allele carriers was not significant for any of the groups using a Bonferroni corrected alpha of.0125. However, chi-square analysis of those carrying any 5 to 8 allele versus noncarriers was significant for pathological gambling (p <.0001), ADHD (p </=.01) and the total index group (p </=.0004). When the comparison included all 7 alleles the results were significant for gamblers (p <.0001), TS (p </=.003), ADHD (p </=.003), and the total group (p </=.0002). There was a significant increase in the frequency of heterozygosity versus homozygosity for all alleles for pathological gamblers (p </=.0031) and the total index group (p </=.0015), suggesting that heterosis played a role. In the substance abuse subjects a quantitative summary variable for the severity of drug dependence, based on the Addiction Severity Index, showed that the scores varied by increasing severity across the following genotypes: 44 </= heterozygotes </= 77 </= 22. Studies of other quantitative traits indicated an important role for the 2 allele and the 22, 24, and 27 genotypes. All studies indicated that the role of the DRD4 gene in impulsive, compulsive, addictive behaviors is more complex than a sole focus on the 7 versus non-7 alleles.