Large scale clinical exome sequencing uncovers the scope and severity of skin disorders associated with MC1R genetic variants

PURPOSE: Genetic variation in MC1R is a main determinant of red hair color (RHC) phenotype which confers susceptibility to skin disorders. METHODS: We assessed the effects and function of MC1R variants identified in our clinical cohort of 135,947 participants with available exome sequencing using phenome-wide association scan (PheWAS). Expression and function of several variants was evaluated. RESULTS: We found 24 nonsense and 215 missense variants in MC1R. Many common missense MC1R variants are strongly associated with skin disorders including skin cancer; however, each variant shows different penetrance and expressivity. Severity of skin phenotype was well correlated with the magnitude of functional defect measured as receptor expression and α-MSH stimulated cAMP production. Remarkably, MC1R deletions and nonsense variants are only weakly associated with milder skin phenotypes. CONCLUSION: Our comprehensive assessment of all MC1R variants in a large cohort clearly establish that individuals with some missense variants are more susceptible to severe skin disorders than those with MC1R deletions or nonsense variants.