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Abstract
This dissertation examines how the effects of genetic variation on human traits are influenced by ancestry and environment, providing new insights into the diversity of inherited genetic and epigenetic associations with human traits across tissue types and diverse populations. Using data from three arsenic-exposed cohorts from diverse ancestry groups, we identified shared and population-specific causal variants driving the association between inherited genetic variation in the 10q24.32/AS3MT (arsenic methyltransferase) gene region and arsenic metabolism efficiency (AME). We further examined the mechanisms by which these variants influence AME and identified the tissues in which these effects are observed. To further explore the tissue-specific nature of the inherited genetic regulation of complex traits, we used data from the Genotype-Tissue Expression (GTEx) project to characterize the effects of single nucleotide polymorphisms (SNPs) on telomere length in and across diverse tissue types. Finally, we pivoted from inherited genetic variation and identified the changes in DNA methylation that accompany prostate cancer (PCa) development and improved our understanding of the biological mechanisms underlying PCa disparities between men of African American (AA) and European American (EA) ancestry. Here, we identified differences in DNA methylation between tumor and benign tissue in each ancestry group as well as differences associated with ancestry. Together, these projects help characterize the diverse impact of inherited genetic and epigenetic associations across ancestries and environments, providing further evidence of the complex nature of genetic associations with human traits.
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