Here, in contrast to the observation for the non-synonymous MC4R polymorphisms Val103Ile and Ile251Leu, the combination of all functional mutations (n = 15) resulted in an additional independent obesity-association signal for the mutations (p-values≤0.05 in model 2 analyzing the mutations only and model 3 joint modelling of distant SNPs, the non-synonymous MC4R polymorphisms and the mutations; Table 5 right panel) which was even strengthened (RR 2.57 to 2.91) upon inclusion of the polymorphisms. The gene discussed is MC4R; the disease is obesity due to melanocortin 4 receptor deficiency.