The environment has a direct effect on human phenotypes and can modify genetic effects on phenotypes through gene-environment interactions (GxE). We apply functional genomics approaches to characterize GxE interactions at the cellular level and understand their role in complex traits. Within these projects, we have developed novel experimental and computational approaches to screen, analyze and functionally characterize genetic variants for complex traits modulated by environmental exposure (Harvey et al, Bioinformatics, 2014, Moyerbrailean et al, Scientific Reports, 2015). We characterized the transcriptional and RNA-processing response to 250 cellular environments. We identified transcription factors that regulate variation in usage of the transcription start site (TSS) in response to environmental perturbations and across different individuals (Richards et al, PLOS Genetics, 2017). We demonstrated a major role for GxE interactions in complex traits (Moyerbrailean et al, Genome Research, 2016; http://genome.grid.wayne.edu/gxebrowser/). We are now using ATAC-seq to analyze the factors and fine map the casual variants for GxE. Additionally, we are using single-cell genomics to analyze GxE in heterogeneous tissues.