Array-Based Epigenetic Aging Indices May Be Racially Biased

Epigenetic aging (EA) indices are frequently used as predictors of mortality and other important health outcomes. However, each of the commonly used array-based indices has significant heritable components which could tag ethnicity and potentially confound comparisons across racial and ethnic groups. To determine if this was possible, we examined the relationship of DNA methylation in cord blood from 203 newborns (112 African American (AA) and 91 White) at the 513 probes from the Levine PhenoAge Epigenetic Aging index to ethnicity. Then, we examined all sites significantly associated with race in the newborn sample to determine if they were also associated with an index of ethnic genetic heritage in a cohort of 505 AA adults. After Bonferroni correction, methylation at 50 CpG sites was significantly associated with ethnicity in the newborn cohort. The five most significant sites predicted ancestry with a receiver operator characteristic area under the curve of 0.97. Examination of the top 50 sites in the AA adult cohort showed that methylation status at 11 of those sites was also associated with percentage European ancestry. We conclude that the Levine PhenoAge Index is influenced by cryptic ethnic-specific genetic influences. This influence may extend to similarly constructed EA indices and bias cross-race comparisons.