The transcriptomic context of DRD1 is associated with prefrontal activity and behavior during working memory

Dopamine D1 receptor (D1R) signaling shapes prefrontal cortex (PFC) activity during working memory (WM). Previous reports found higher WM performance associated with alleles linked to greater expression of the gene coding for D1Rs (DRD1). However, there is no evidence on the relationship between genetic modulation of DRD1 expression in PFC and patterns of prefrontal activity during WM. Furthermore, pre- vious studies have not considered that D1Rs are part of a coregulated molecular environment, which may contribute to D1R-related prefron- tal WM processing. Thus, we hypothesized a reciprocal link between a coregulated (i.e., coexpressed) molecular network including DRD1 and PFC activity. To explore this relationship, we used three indepen- dent postmortem prefrontal mRNA datasets (total n = 404) to char- acterize a coexpression network including DRD1. Then, we indexed network coexpression using a measure (polygenic coexpression index—DRD1-PCI) combining the effect of single nucleotide polymor- phisms (SNPs) on coexpression. Finally, we associated the DRD1-PCI with WM performance and related brain activity in independent sam- ples of healthy participants (total n = 371). We identified and repli- cated a coexpression network including DRD1, whose coexpression was correlated with DRD1-PCI. We also found that DRD1-PCI was associated with lower PFC activity and higher WM performance. Be- havioral and imaging results were replicated in independent samples. These findings suggest that genetically predicted expression of DRD1 and of its coexpression partners stratifies healthy individuals in terms of WM performance and related prefrontal activity. They also high- light genes and SNPs potentially relevant to pharmacological trials aimed to test cognitive enhancers modulating DRD1 signaling.