Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviours: Tourette syndrome, ADHD, pathological gambling, and substance abuse

Prior studies have reported an association between the presence of the 7 re peat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, atte ntion deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathol ogical gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine whether we could replic ate these associations we genotyped 737 individuals from four different gro ups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pat hological gambling, TS, and (ADHD). Chi-square analysis of those carrying t he 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 an alysis of those carrying any 5 to 8 allele versus noncarriers was significa nt for pathological gambling (p < .0001), ADHD (p less than or equal to .01 ) and the total index group (p less than or equal to .0004). When the compa rison included all 7 alleles the results were significant; for gamblers (p < .0001), TS (p less than or equal to .003), ADHD (p less than or equal to .003), and the total group (p less than or equal to .0002). There was a sig nificant increase in the frequency of heterozygosity versus homozygosity fo r all alleles for pathological gamblers (p less than or equal to .0031) and the total index group (p less than or equal to .0015), suggesting that het erosis played a role. In the substance abuse subjects a quantitative summar y variable for the severity of drug dependence, based on the Addiction Seve rity Index, showed that the scores varied by increasing severity across the following genotypes: 44 less than or equal to heterozygotes less than or e qual to 77 less than or equal to 22. Studies of other quantitative traits i ndicated an important role for the 2 allele and the 22, 24, and 27 genotype s. All studies indicated that the role of the DRD4 gene in impulsive, compu lsive, addictive behaviors is more complex than a sole focus on the 7 versu s non-7 alleles, Am. J, Med. Genet. (Neuropsychiatr. Genet.)88:358-368, 199 9. (C) 1999 Wiley-Liss, Inc.