Precision Medicine Technologies
Systematic Data-Based Approaches for Precision Medicine
Schizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. We consider the successes and limitations in applying hiPSC-based models to study the impact of rare and common variants in SZ risk. First, we evaluated the impact of patient-specific NRXN1+/- deletions in hiPSC-neurons, observing greater than two-fold reduction of half of the wildtype NRXN1α isoforms and detecting dozens of novel isoforms expressed from the mutant allele; reduced neuronal activity in patient hiPSC-neurons was ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decreased neuronal activity levels in control hiPSC-neurons. Second, by integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative causal SZ SNP (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our hiPSC-based neuronal platform resolved uncovered an unexpected synergistic effect between SZ-eQTL genes that converges on synaptic function and links the rare and common variant genes implicated in psychiatric disease risk, one which may represent a generalizable phenomenon occurring more widely in complex genetic disorders. We demonstrate a systematic and scalable strategy to interpret and evaluate the growing number of SZ-associated variants and genes across neural cell types and genetic backgrounds. Altogether, our objective is to dissect the genetic origins of SZ while developing a precision medicine approach to screen for novel therapeutics with which to prevent or reverse disease course.