Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2)

Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most frequently studied candidate variant for addiction in DRD2 for association with brain structure. We tested whether this variant showed associations with regional brain volumes across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1). We hypothesized that this addiction-related polymorphism would be associated with structural brain differences in regions previously implicated in familial vulnerability for drug dependence. Then, we assessed the generalizability of our findings by testing this polymorphism in a non-overlapping replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. In both cohorts, the minor allele—previously linked with increased risk for addiction—was associated with larger volumes in various brain regions implicated in reward processing. These findings suggest that neuroanatomical phenotypes associated with familial vulnerability for drug dependence may be partially mediated by DRD2 genotype.