A systematic review and a meta-analysis of genetic studies linking dopaminergic alleles to aggression: Where are we now?

Dopaminergic neurons innervate brain regions that play a crucial role in aggressive behavior as they are involved in reinforcement learning, decision-making, and behavioral control. Genetic studies suggest that polymorphisms in dopaminergic genes may contribute to individual differences in aggression, but results from these studies are often inconsistent due to limited sample sizes and lack of replication. To our knowledge, this systematic review and meta-analysis represents the first endeavor to comprehensively collect, interpret, and compare genetic studies linking dopaminergic alleles to aggression. Our critical revision of candidate-gene studies revealed that the most robust association with aggressive behavior concerned the 7-repeat allele of DRD4 48 bp variable number of tandem repeats (VNTR) in White individuals exposed to prenatal stress or childhood maltreatment. The meta-analysis confirmed the robustness of this association, indicating a small but significant effect, and supporting the hypothesis that carriers of the 7-repeat allele are more susceptible to developing aggressive behaviors when exposed to early negative environmental conditions. This finding was not replicated by genome-wide association studies (GWASs), as they did not examine VNTRs. However, GWASs revealed glutamatergic variants functionally connected to dopaminergic receptors as associated with aggressive behavior. These findings are consistent with the dopaminergic and glutamatergic impairment hypothesis of aggressive behavior, but larger-scale genome-wide studies covering both common and rare genetic variants and contemplating gene-environment interactions are required to deeply understand the complex and multifactorial nature of aggression.