This 8 point difference is clinically meaningful, as it is larger than the difference between most categories . An additional interesting aspect of the current study was that the genetic risk score was related to the severity of depressive symptoms in two groups with wide-ranging depression scores, with a lower score related to higher depression both in healthy undergraduates and in patients with a diagnosis of depression. Future studies can examine the robustness of the genetic risk score across other conditions related to dopamine neurotransmission, where it might have utility, for example, to provide insights in the setting of Parkinson’s disease, where inter-individual response to dopaminergic therapy is highly variable. Theoretically, the dopamine genetic risk score could inform the likelihood that a drug with dopaminergic activity would be an effective antidepressant treatment choice for an individual patient. Despite its strengths, the study has a number of limitations. First, there was heterogeneity across the samples, with the two replication samples having different measures of depressive symptoms and different genes comprising the genetic risk score when compared to the discovery cohort. For example, the genetic score for STAR*D was estimated based on imputed SNPs, compared to the discovery sample, which was based on genotyped SNPs. Second, replication in the second healthy adult cohort failed to reach statistical significance, although results trended in the same direction as with the two other cohorts. This finding might reflect the fact that the 5-item POMS depression subscale used in the GSP, which measures only current mood state, lacked sufficient sensitivity to detect an association with the dopamine genetic risk score. It may also reflect the phenomenon known as the “winner’s curse”, whereby the effect of our genetic risk score could have been exaggerated in the discovery sample compared to the two replication studies. Future studies may be able to address this issue by examining more detailed measures of depressive symptoms or its specific features as well as by examining whether the genetic risk score predicts diagnoses of depression rather than depressive symptoms. Third, the direction of correlation between the DAT 9/10 polymorphism and depression is in the opposite direction of that found in a meta-analysis by Lopez-Leon. Mixed results are common with this polymorphism and the reason for the discrepancy is unclear. Fourth, dopamine effects are influenced by numerous factors such as the dynamics and concentration of its release, issues not examined in the current study. Fifth, although a great deal of evidence indicates that environmental factors may interact with genetic susceptibility to produce the final affective/behavioral phenotype, i.e, whether or not an individual will develop depression, we did not examine geneenvironment interactions in this study.