Of the 31 genes linked with severe monogenic obesity or lipodystrophy,6,81 three (PPARG, PLIN1, and MC4R) are associated with an obesity or fat distribution trait at the exome-wide level (p < 1.58 × 10−7) in our rare-variant gene-level association testing, representing a 125-fold enrichment over random chance (Fisher’s exact test p = 3.87 × 10−6). Here, PLIN1 is linked to obesity due to melanocortin 4 receptor deficiency.