Traditional analyses of rare genetic mutations are performed by comparing heterozygous mutation carriers to noncarriers. An important example is the p.Tyr35Ter premature stop codon present in 0.02% of the population and typically inherited as a shared haplotype with the p.Asp37Val missense mutation, which has been previously shown to completely inactivate MC4R activity in in vitro functional assays (Larsen et al., 2005; Xiang et al., 2006). A recent analysis linked this variant to an average weight increase of 7 kilograms (Turcot et al., 2018).
