Functional genomics of psychiatric disease risk using genome engineering

As the complex genetics underlying risk for psychiatric disorders are uncovered, the translation of genetic findings to inform our understanding of disease pathophysiology and treatment is an urgent and important challenge. Human induced pluripotent stem cell (hiPSC)-based models provide a source of live human donor-specific neurons and glia, while CRISPR-based methods make it possible to precisely engineer and manipulate the genome and epigenome. Together, these emerging technologies make possible the functional exploration of the fundamental roles of risk variants and genes linked to psychiatric disease. Here, we provide a brief overview of the genetic risk architecture associated with psychiatric disorders, highlight relevant technical advancements in hiPSC models and CRISPR engineering that make possible new avenues to empirically evaluate the functional impact of risk variants in disease-relevant cell types. We next assess novel applications combining hiPSC-based approaches and genetic screening to uncover the effect of risk variants at unparalleled scale and culminate with a critical appraisal of the developments necessary to translate new insights into clinically actionable information and novel therapeutic approaches.