Many of our associated loci highlight genes that are highly expressed in the brain (and several particularly so in the hypothalamus), consistent with an important role for CNS processes in weight regulation. We found that TMEM18, KCTD15, SH2B1, GNPDA2 and NEGR1 are expressed at high levels in brain and hypothalamus (as are FTO and MC4R; Supplementary Fig. 3). The remaining gene, MTCH2, has evidence of expression in the brain in published data27, as does BDNF28, a locus identified by Thorleifsson et al.12. These results extend and confirm previous observations with respect to FTO and MC4R, and are consistent with insights derived from monogenic forms of obesity and functional studies. Disruption in mice of Mc4r, Sh2b1 and Bdnf (all genes that seem to be involved in signaling in the brain) results in hyperphagia and/or obesity, and both Fto and Sh2b1 show diet- or obesity-related changes in expression in hypothalamus21,29-34. Further general support for a neuronal basis for obesity comes from the observation that NEGR1 is thought to affect neuronal outgrowth24,25. Finally, the effect of variants that map to a gene desert
