The aim of this study is to determine the allele and genotype frequency of peroxisome proliferator-activated receptor-γ (PPARγ) rs1801282, fat mass and obesity-associated protein (FTO) rs9939609, and melanocortin 4 receptor (MC4R) rs2229616 polymorphisms and their association with risk of T2DM in the western Saudi population as mediators of adiposity phenotypes. Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.