Fig. 1. Schematic overview of workflow.

We first conducted differential expression analysis to identify genes whose expression is correlated with glucose and lipid traits. We then used these trait correlations in combination with a coexpression analysis to identify a GLD module that simultaneously regulates both glucose metabolism and lipid metabolism. We replicated this analysis in a mouse model and two additional human cohorts and found equivalent modules in each. We performed causal inference and key driver analysis on the GLD module to identify master regulator genes including LSS. Finally, we inhibited Lss in a mouse model to demonstrate the function of the GLD module.