ORMDL3 and obesity due to melanocortin 4 receptor deficiency: Through the integration of multilayer genomics data in a functionally relevant human cell type and tissue and replication in the GTEx and TwinsUK cohorts, we show that the DHSs within the interacting chromosomal regions are enriched for tissue-specific TF motifs and explain a significant proportion of the heritability of gene expression in cis. Furthermore, we identified LACTB, ACADS, ORMDL3, and MAP2K5 as obesity-related genes in humans and provide a set of 38 non-GWAS candidate genes for future studies in obesity.