Additionally, within the 20 associated regions, we confirmed two previously published obesity associations: CNVR 1p31.1 20 kb upstream of NEGR1 (7,8) and CNVR 10q11.22 (1) covering the four genes SYT15, GPRIN2, LOC728643 and PPYR1 (19) with PPYR1 being the most interesting candidate, given its role in energy homeostasis and regulation of food intake (27,32). PPYR1 null animals have, for instance, a reduced body weight. PP reduces food intake predominantly via stimulation of the anorexigenic melanocortinergic pathway. This effect is mediated by direct action on local PPYR1 within the arcuate nucleus (32). PP binds to the PPYR1. In our study as well as in the previous study which initially described the association of CNVR 10p11.22 (1) with BMI (19), the loss of a PPYR1 gene copy number was associated with obesity. Among those individuals (n = 57) of our two GWAS discovery samples that were called for the loss of a PPYR1 gene copy number, only one was homozygous for the deletion. One can only speculate about these seemingly contradictory findings between studies in human and mice. Several mechanisms might explain
