MOTA, N. R., Bau, C. H. D., Banaschewski, T., Buitelaar, J. K., Ebstein, R. P., Franke, B., Gill, M., Kuntsi, J., Manor, I., Miranda, A., Mulas, F.,Oades, R. D., Roeyers H., Rothenberger, A., Sergeant, J. A., Sonuga-Barke, E. J. S., Steinhausen, H-C., Faraone, S. V., & Asherson, P.,

Association between DRD2/DRD4 interaction and Conduct Disorder: a potential developmental pathway to alcohol dependence. American Journal of Medical Genetics Part B, 162, 546-549. [Request a copy] ..... View Article

Introduction: The DRD2 & DRD4 polymorphisms (for dopaminergic receptors) investigated interact with each other.

The expression ratio of the short-(D2S) & long-(D2L) DRD2 isoforms (mainly presynaptic & postsynaptic, respectively) are affected by the DRD2 rs2283265 SNP, where the minor allele (T) favours the expression of the D2L form. This allele has been associated in previous studies with cocaine abuse, reduced WM and attention control performance.

For the DRD4 48-bp VNTR polymorphism in exon 3 the most common variants are the 2-, 4- and 7-repeats (2R, 4R and 7R, respectively), with 7R being implicated in ADHD.

Methods: Subjects were classified according to the presence of the DRD2 and DRD4 risk alleles (T & 7R, respectively) and, as in the previous studies, subjects with rare DRD4 alleles (not 2R, 4R or 7R) were excluded from all analyses; all presented p-values are two-tailed. Chi-squared tests were first used to test association of each SNP separately with Conduct Disorder (CD).

1 - The presence of the T allele of the DRD2 rs2283265 SNP was associated with higher prevalence of CD (X2=5.66, p<0.02), but there was no effect of the DRD4 7R allele (X2=0.057, p=0.81).

2 - Next, logistic regression revealed a significant DRD2-DRD4 interaction (p=0.041) associated with CD.

3 - Estimation of the odds ratio (OR) in the presence of interaction was performed. The findings indicated that the presence of the DRD2 T allele conferred an increased risk of CD (OR CI_95= 2.33 (1.41-3.86)) for Ss that did not have the DRD4 7R allele, whereas there was no risk associated with the DRD2 T allele for non-carriers of DRD4 7R (OR CI_95= 0.96 (0.48-1.91)).


a) This DRD2-DRD4 interaction pattern is similar to the previously reported association with alcohol dependence in adults with and without ADHD.

b) In the earlier study, the concomitant presence of both DRD2-T & DRD4-7R alleles was associated with a protective effect, compared to the presence of either one of them alone (i.e. in the absence of the other).

c) In keeping with this observation, current results suggest that the significantly increased risk conferred by the DRD2 T allele is suppressed by the concomitant presence of the DRD4 7R risk allele.

d) The findings of the DRD2-DRD4 interaction association with childhood/adolescent CD, a frequent precursor of later SUD, suggests a potential mechanism for one possible causal pathway that links childhood conduct disorder to the later development of alcohol dependency.