This gene-level integrative genomics approach successfully re-captured the direction-of-effect and tissue specificity of several well-characterized insulin resistance effector genes, including LPL, PPARG and ANGPTL4, as well as a more recently characterized gene COBLL1. Gene-level burden tests showed that loss-of-function (LOF) protein-coding variation in LPL and PPARG is associated with an increase in TG/HDL (LPL: effect size = 0.04, p = 3.1 × 10−23; PPARG: effect size = 0.04, p = 5 × 10−6), consistent with the well-characterized roles of LPL and PPARG in insulin resistance43,52. Here, ANGPTL4 is linked to Insulin resistance.