Abstract: Detailed characterization of molecular and cellular effects of genetic variants is essential for understanding biological processes that underlie genetic associations to disease. A particularly scalable approach has been linking genetic variants to effects in the transcriptome that is amenable for scalable measurements in human populations and in experimental settings, including at the single-cell level. Our multi-omic analysis in human cohorts in the TOPMed project has identified genetic and environmental effects on molecular variation together with their complex interplay with clinical phenotypes. Furthermore, in this talk, I will discuss how CRISPRi silencing of regulatory elements followed by single-cell analysis provides novel insights into mechanisms of genetic associations to complex traits. Altogether, these diverse approaches to the integration genome and transcriptome data uncover the functional genetic architecture of human traits and enhances our understanding of both basic biology and precision medicine applications.