Access Type

Dissertation/Thesis

Date of Award

January 2021

Degree Type

Dissertation

Degree Name

Pharm.D./Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Francesca Luca

Second Advisor

Roger Pique-Regi

Abstract

Complex traits and diseases are thought to be the result of the combined effects of genetic predispositions, environmental factors, and their interactions. Therefore, the goal of the modern approach to patient care – precision medicine – is to devise treatment and prevention plans tailored to each individual’s genetics, environment, and lifestyle. However, measuring genotype-by-environment (GxE) effects on complex traits using epidemiological approaches is intractable and error-prone. Thus, scientists are increasingly turning to studying quantitative molecular phenotypes upstream of the organismal trait but directly causal to it, such as gene expression, to detect GxE effects and relate them to complex traits. This dissertation extends this body of knowledge by investigating GxE effects at three crucial levels of resolution: broad external environments, endogenous factors, and molecular stimuli.In Chapter 2 I used a new machine learning approach to identify leukocyte transcriptional signatures of 19 variables including psychosocial factors, blood cell composition and asthma symptoms, and found 174 genes associated with asthma that are regulated by psychosocial factors, and 349 significant gene-environment interactions for gene expression levels, including GxE effects of psychosocial experiences on the expression of seven genes implicated in asthma and allergic disease. In Chapter 3 I used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated PBMCs from 96 African American individuals. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and identified genetic variants regulating gene expression of 1673 and gene expression variability of 98 genes, including treatment-specific effects. In Chapter 4 I used longitudinal data to demonstrate that age effects on gene expression are largely shared between peri-pubertal boys and girls, but pubertal development is more strongly reflected in immune cell gene expression in girls than in boys. Further, I identified five genetic variants that modify the association between pubertal development and gene expression, including effects on immune response genes. Together, this work advances our understanding of the modulating effects of various types of environments on genetic regulation of gene expression, and the potential consequences for health and disease.

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