Based on such findings, dopaminergic targets have become a focus for depression therapies; one study found that the DRD2 agonist pramipexole was as effective as fluoxetine in the treatment of MDD. Thus, a decreased level of endogenous dopaminergic neurotransmission might make a significant contribution to depression pathology. Another method by which decreased dopaminergic neurotransmission might increase depressive symptoms is through its influence on motivation and reward processing, both of which are impaired in depression. Examination of the effect of dopamine-related genetic variants may extend knowledge of the role of dopamine neurotransmission in the etiology and course of depression. This line of research is warranted, as depression is highly heritable and several genetic variants have been found to modulate endogenous dopamine neurotransmission. Thus far, evidence on the role of variation in dopamine neurotransmission in depression has been mixed. While some studies find that dopamine-related variants are associated with multiple psychiatric and neurological diseases, other studies find no association. Moreover, when dopamine-related polymorphisms have been studied in the context of genome-wide association studies, none have emerged as significantly associated with depression. One likely contributor to these inconsistent findings is that common genetic variants for complex disease tend to have small to modest effects. Thus, tests of association based on a single nucleotide polymorphism are unlikely to yield significant effects unless very large samples are studied. We sought to provide additional evidence regarding the role of dopamine in depression by examining the combined effect of five dopamine-related polymorphisms and depressive symptom severity. We used a genetic risk score approach, which sums the effects of multiple polymorphisms in the same biological system. Genetic risk score approaches have been informative in several medical and psychiatric settings, including when studying the role of dopamine. The genetic risk score employed in the current study captures genetic variation in several aspects of the brain dopamine system, including synaptic dopamine availability and dopamine receptor binding. These proteins are abundant in the cortical and subcortical neural structures affected in depressive disorders. The genetic risk score employed in this analysis has been linked to learning a motor skill and the extent to which oral Ldopa supplementation improves this learning. Given its public health burden, there is an urgent need to better understand the etiology of depression and deploy this knowledge to inform the development and implementation of effective prevention and treatment efforts. However, depression is widely considered to be a heterogeneous disorder consisting of multiple subtypes and symptom clusters, which can reflect a number of different underlying brain states.