Significance Dopamine D ₁ receptors in the prefrontal cortex (PFC) are critical for working memory (WM). However, it is unknown how D ₁ -related genetic background mediates differences in WM performance between humans. Furthermore, previous studies did not consider that DRD1 is likely part of a coregulated molecular network, which may contribute to WM performance and its underlying neural correlates. The key of this research is the identification of a relationship between genetically predicted coexpression and WM processing. In particular, genetically predicted greater DRD1 -related coexpression was associated with lower PFC activity and higher WM performance, indicating greater WM efficiency. Our findings may help to link gene expression with brain activity and to develop WM-enhancing drugs by differentiating individuals based on their genetic background.