Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

Abstract Understanding the molecular and organismal function of genetic variants in non-coding regions is crucial to dissect the genetic and evolutionary basis of variation in complex traits. As we and others have shown, the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by the environmental context (gene-environment interactions, GxE). Most contexts considered to date focus on aspects of the physical environment that can be reproduced in vitro (e.g., pathogen particles, hormones, toxicants). We also pioneered the study of GxE with psychosocial experiences (e.g., socio-economic status, neighborhood stress). Importantly, psychosocial experiences can influence an individual's ability to respond to other environmental challenges and these effects can be measured at the cellular level. However the effects of psychosocial experiences on the transcriptional response to cellular stressors has not been fully evaluated. The response to environmental challenges is often mediated by changes in transcription factor activity. Single cell genomics technology has allowed us to discover that gene regulatory changes in response to environmental perturbations are often heterogeneous both across cell types, and across individual cells within a cell type, resulting in a dynamic response. This dynamic response can in turn be regulated through GxE, and it's an important contributor to disease risk. To study the dynamic gene regulatory response to chemical and social stressors, here we will focus on peripheral blood mononuclear cells from an inner city cohort of middle-aged adults collected as part of The Heart of Detroit Study (THDS) and consider psychosocial and cellular stressors. One of the main objectives of this project will be to develop functional genomics, computational, and statistical approaches to dissect the epigenetic mechanisms underlying the response to in vitro and in vivo stressors, their interactions with genetic variants, and ultimately their role in complex trait variation. The tools developed in this project will have broad applicability in the fields of functional genomics, systems biology, and GxE, ultimately allowing for a global and integrative analysis of genetic and environmental effects on biological systems.