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



Genetic variation in MC1R is a main determinant of red hair color (RHC) phenotype and confers susceptibility to skin disorders.


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 were evaluated.


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.


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.

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Fig. 1: Phenome-wide association scan (PheWAS) for 10 common variants of MC1R, 9 missense variants, and 1 nonsense MC1R variant.
Fig. 2: Heat map of odds ratios from phenome-wide association scan (PheWAS) of common MC1R variants shows the association of MC1R common variants with neoplasms of skin or dermatologic phenotypes.
Fig. 3: In vitro functional data for missense variants with MAF > 0.005.
Fig. 4: Relationship of neoplasms and functional consequences of common MC1R missense variants.
Fig. 5: Relationship of dermatologic clinical traits and functional consequences of common MC1R missense variants.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Data files. Additional information for reproducing the results described in the article is available upon reasonable request and subject to a data use agreement.


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This work was supported by GM111913 to T.M. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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B.S.M. performed experiments, analyzed data, prepared draft manuscript, cowrote final manuscript. J.Z.L. performed PheWAS and SKAT-O analyses, prepared draft manuscript. A.N.S. performed experiments, analyzed data; T.M. conceptualized and supervised the study, cowrote final manuscript. Conceptualization: B.S.M., T.M. Data curation: J.Z.L. Formal analysis: J.Z.L. Funding acquisition: T.M. Investigation: B.S.M., A.N.S. Writing—original draft: B.S.M. Writing—review & editing: B.S.M., T.M.

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Correspondence to Tooraj Mirshahi.

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The authors declare no competing interests.

Ethics declaration

This research was approved by the Geisinger Clinic Institutional Review Board and included 135,947 participants in the MyCode Health Initiative who have exome sequencing data obtained as part of the Geisinger-Regeneron DiscovEHR collaboration. All participants provided written informed consent, and all experiments were performed in accordance with relevant guidelines and regulations. The authors did not have access to any identifying information for the participants. The human phenotype and genotype data in this study were all de-identified by a data broker who was not involved in the study before any analysis was performed. De-identified clinical data were obtained from EHRs.

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Moore, B.S., Luo, J.Z., Stepanchick, A.N. et al. Large scale clinical exome sequencing uncovers the scope and severity of skin disorders associated with MC1R genetic variants. Genet Med 23, 2386–2393 (2021).

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