The causes of human obesity, insulin resistance, and MASLD are incompletely understood, limiting ourability to treat these conditions. We carried out GWAS analyses of overall obesity, abdominal obesity, insulin resistance, and MASLD and identified thousands of genetic variants that affect these traits in humans. We mapped them to tissues, pathways, and genes and evaluated their biochemical effects in human cell lines and mice. We showed that the nervous system, appetite regulation, energy metabolism, neuronal biology and targets such as MC4R, GLP-1R, GRP, and CALCR affect overall obesity. We showed that adipose biology and mesoderm develop, cell growth & survival, and glucocorticoid receptor signaling and targets such as PPARG affect abdominal obesity. We showed that liver, intestine, pancreas and adrenal, lipoprotein, triglyceride and arachidonic acid metabolism and targets such as PNPLA3 affect MASLD. We showed that adipose tissue, lipid homeostasis, brain processes, adipogenesis, brain/growth and targets such as GRB14 affect insulin resistance. Variation in a non-coding gene can cause a glycogen storage disease in humans that predisposes to metabolic syndrome, but not heart attack. We defined MASLD genetic subtypes and genes to treat them for precision medicine. We showed that insulin resistance combines with genetic risk to promote MASLD and identified characteristics of individuals with high risk of incident cirrhosis. By combining human genetics and functional studies we have elucidated the causes of overall obesity, abdominal obesity, MASLD, and insulin resistance and identified many new targets for therapeutic intervention.