Beyond Melanoma: Skin Color and Disease Risk

The role of pigmentation in human skin is not limited to photoprotection, but - shaped by evolutionary and developmental pressures - mediates a number of important health outcomes. Melanin is well known to scatter ultraviolet radiation (UVR), thus protecting dermal cells from this potent mutagen.  However, the scattering of UVR also reduces the synthesis of vitamin D in the blood. Vitamin D deficiency has been associated with several disorders at increased frequency among minority groups in the U.S., including cardiovascular disease, type II diabetes, and some types of cancer. Because pigmentation is correlated with biogeographic ancestry as well as cultural definitions of race, vitamin D levels may contribute to health disparities.  The role of vitamin D deficiency in negative health outcomes may be magnified in the coming decades given the twin factors of increased global mobility – leading to more dark-skinned individuals living in locations with lower UVR levels – and increasingly urban and sedentary lifestyles – which decrease exposure to sunlight.  While realized pigmentation influences vitamin D levels, the intertwined developmental pathways of the nervous and pigmentary systems also have the potential for pleiotropic effects and genetic constraints on these domains. As a result, gene-set enrichment analysis, a method for assessing families of genes with many small, individual effects on a phenotype, reveals a disproportionately large number of neurological genes associated with skin color.

Because of the broad range of skin color variation and genetic heterogeneity, admixed populations in the U.S. are ideal for the genetic study of both skin color and its relationship to non-dermatological disease risk through these unexpected avenues.  Numerous studies have considered vitamin D levels and health outcomes in African Americans while fewer have considered the influence of pigmentation on neurological disorders.  This relationship is highlighted by the link between a known opioid receptor gene, OPRM1, and skin pigmentation in Hispanic populations and an association between nicotine addiction and skin pigmentation seen in African Americans.  Disentangling the complex influences of natural selection, biogeographic ancestry, and environment on skin color is challenging, but likely to have significant health effects for millions of people world-wide.