The newly discovered variants showing strong associations with BMI lie in or downstream of KCTD15, SH2B1, TMEM18, MTCH2 and GNPDA2, and upstream of NEGR1 (Fig. 2). SH2B1 is a strong prior candidate for regulating body weight. SH2B1 is implicated in leptin signaling21, and Sh2b1-null mice are obese21. Notably, the obesity in Sh2b1-null mice can be reversed by targeted Sh2b1 expression in neurons21, suggesting that the effects of this gene on obesity are mediated through the CNS. KCTD15, TMEM18 and GNPDA2 have unknown functions, whereas MTCH2 encodes a putative mitochondrial carrier protein that may function in cellular apoptosis22,23, and NEGR1 has a role in neuronal outgrowth24,25. Although fine mapping and other experimental approaches will be required to identify and confirm the causal variant(s) and gene(s) for each locus, we note that, with the exception of SH2B1, our newly associated loci do not include obvious or previously studied candidate genes26. Thus, a large sample size and an unbiased genome-wide approach has not only increased the number of known obesity loci, but also highlighted new aspects of the biology of body weight regulation.
