function, cell–cell adhesion, and glutamate signalling (ELAVL4, GRID1, CADM2, NRXN3, NEGR1 and SCG3), cause monogenic obesity syndromes (MC4R, BDNF, BBS4 and POMC), or function in extreme/early onset obesity in humans and mouse models (SH2B1 and NEGR1)6,28,29. Other genes with several lines of supporting evidence are related to insulin secretion and action, energy metabolism, lipid biology, and/or adipogenesis (TCF7L2, GIPR, IRS1, FOXO3, ASB4, RPTOR, NPC1, CREB1, FAM57B, APOBR and HSD17B12), encode RNA binding/processing proteins (PTBP2, ELAVL4, CELF1 and possibly RALYL), are in the MAP kinase signalling pathway (MAP2K5 and MAPK3), or regulate cell proliferation or cell survival (FAIM2, PARK2 and OLFM4). Although we cannot be certain that any individual gene is related to the association at a given locus, the strong enrichment of pathways among genes within associated loci argues for a causal role for these pathways, prioritizes specific genes for follow-up experiments, and provides the strongest genetic evidence so far for a role of particular biological and CNS processes in the regulation of human body mass.
