A plethora of disease relevant genetic loci have been identified by genetic association studies. Jiao and colleagues hypothesized that perturbing these loci/genes in adipocytes in vitro and assessing the effect on morphologic features would enable disease relevant functional annotation. Here, they demonstrate the utility of this approach in metabolic disease. They ablated 125 genes in human pre-adipocytes using CRISPR/CAS9 and profiled the effect on cellular morphology using morphologic similarity to identify mechanistic interactions between genes. They demonstrate that this morphometric approach is capable of surveying diverse cellular mechanisms by validating both a protein-protein interaction on the lipid droplet surface and a transcriptional regulatory interaction in the DNA.