We found a 3-locus model involving 3 genes of INSIG-SCAP-SREBP pathway (INSIG2 rs9308762, SCAP rs12487736, and SREBP2 rs1883205) had significant gene-gene interaction on obesity (permutated P = 0.001). Here, INSIG2 is linked to obesity due to melanocortin 4 receptor deficiency.