Dopamine D2 receptors (D2Rs) contribute to the inverted U-shaped relationship between dopamine signaling and prefrontal function. Genetic networks from post-mortem human brain revealed 84 partner genes co-expressed with DRD2. Moreover, eight functional single nucleotide polymorphisms combined into a polygenic co-expression index (PCI) predicted co-expression of this DRD2 network and were associated with prefrontal function in humans. Here, we investigated the non-linear association of the PCI with behavioral and Working Memory (WM) related brain response to pharmacological D2Rs stimulation. Fifty healthy volunteers took part in a double-blind, placebo-controlled, functional MRI (fMRI) study with bromocriptine and performed the N-Back task. The PCI by drug interaction was significant on both WM behavioral scores (P = 0.046) and related prefrontal activity (all corrected P < 0.05) using a polynomial PCI model. Non-linear responses under placebo were reversed by bromocriptine administration. fMRI results on placebo were replicated in an independent sample of 50 participants who did not receive drug administration (P = 0.034). These results match earlier evidence in non-human primates and confirm the physiological relevance of this DRD2 co-expression network. Results show that in healthy subjects, different alleles evaluated as an ensemble are associated with non-linear prefrontal responses. Therefore, brain response to a dopaminergic drug may depend on a complex system of allelic patterns associated with DRD2 co-expression.