Genetic Regulation of Gene Expression in African Americans

Zhong, Yizhen

doi:https://doi.org/10.21985/n2-r0gd-p574

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Genetic Regulation of Gene Expression in African Americans

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Current genetic studies are largely biased towards European populations, leaving the discovery of genomics biomarkers and causative genetic variants unexplored in minority populations, such as African Americans. Meanwhile, African Americans are disproportionately affected by a variety of complex diseases and respond differently to many drug treatments. The disparity is due to the paucity of “omics” data in the African American population as well as the lack of adequate statistical methodologies needed to account for the complexity of their genomes. This thesis provides both the methodological improvements and biological insights through studying the genetic regulation of gene expression in African Americans. Chapter 2 investigates the role of local ancestry in improving expression quantitative trait loci (eQTL) mapping and heritability analysis in admixed and multi-ethnic cohorts and provides a computationally efficient R package (LAMatrix) for incorporating local ancestry into eQTL mapping. Chapter 3 characterizes the genetic architecture of gene expression in African American hepatocytes and demonstrates novel discoveries made through leveraging the greater genetic diversity and less extensive linkage disequilibrium of the African genome. Chapter 4 evaluates the transcriptomic and genetic regulation change upon enzyme induction and presents novel regulatory variants of drug metabolism enzymes that might confer inter-individual differences in drug response. Together, this thesis highlights the importance of biological context in characterizing the genetic effects on gene expression, enhances the understanding of the functional consequences of genetic variants in molecular and phenotypic traits, and helps to reduce health disparities in genomic medicine.

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