9. MODELLING THE IMPACT OF RARE AND COMMON VARIANTS IN SCHIZOPHRENIA USING STEM CELLS

ABSTRACT: Abstract Schizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. Overall, we consider the successes and limitations in applying human induced pluripotent stem cell (hiPSC)-based models to study the impact of rare and common variants in SZ risk. To explore the neuronal impact of rare variants, we investigated the relationship between heterozygous 2p16.3 deletions, alternative splicing of NRXN1, and perturbations in neuronal activity, finding some commonalities with idiopathic SZ. We identified ~100 NRXN1? isoforms in control hiPSC neurons; patient-derived 2p16.3 neurons show perturbed NRXN1 isoform repertoires, reduced neuronal branching and decreased neuronal activity, which unexpectedly can be partially ameliorated by overexpression of a single NRXN1 isoform. Second, we present a genetics-driven hiPSC-based CRISPR-mediated approach for the functional validation of common variants and genes associated with SZ, evaluating the impact of one putative causal SZ SNP (FURIN rs4702) and two SZ-associated genes (SNAP91 and TSNARE1) on global gene expression patterns and synaptic function. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. 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. Concurrent Symposia

SUBMITTER: Brennand K 

PROVIDER: S-EPMC6455771 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature