Furthermore, for a relatively modest difference in BMI (0.4 to 0.9 kg/m2), we observed that β-arrestin-biased GoF alleles in MC4R were associated with a large difference in risk of cardio-metabolic disease outcomes (up to 50% lower risk), more than expected from observational epidemiology studies (Wormser et al., 2011). The gene discussed is MC4R; the disease is metabolic disease.