Humanity in a Dish: Population Genetics with iPSCs

Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype. Recent publications have described iPSC cohort studies of common genetic variants and their effects on gene expression and cellular phenotypes. These in vitro quantitative trait locus (QTL) studies are the first experiments in a new paradigm with great potential: iPSC-based functional population genetic studies. iPSC collections from large cohorts are currently under development to facilitate the next wave of these studies, which have the potential to discover the effects of common genetic variants on cellular phenotypes and to uncover the molecular basis of common genetic diseases. Here, we describe the recent advances in this developing field, and provide a road map for future in vitro functional population genetic studies and trial-in-a-dish experiments. iPSCs are increasingly used for modeling monogenic disease, by using directed differentiation to derive disease-affected cell types carrying causal genotypes. Recent publications have used iPSCs and iPSC-derived functional cells to perform QTL studies; the first use of iPSCs for assessment of common genetic variants and their effect on cellular functions. iPSC-derived hepatocytes and cardiomyocyte cardiotoxicity and hepatotoxicity screens are being developed for use in drug development, potentially increasing accuracy of safety testing, and bringing us closer to the reality of running a trial in a dish. Large cohorts of iPSCs are being reprogrammed and deposited for public use; some of these repositories are currently available; responsible use of such cohorts for productive studies requires careful experimental design.