CRISPR‐based functional evaluation of common SZ risk variants

Schizophrenia (SZ) is a highly heritable neuropsychiatric disorder. Nevertheless, the functional mechanisms through which the large contribution of common genetic variation underlies this disorder remain unclear. GWAS and eQTL analyses have previously identified candidate genes, whose expression is affected by common SZ risk variants (SZ‐eQTL genes). We established a genetics‐driven hiPSC‐based approach for the prioritization and functional validation of common variants and genes associated with SZ. Using this strategy, we prioritized one putative causal SZ‐eQTL SNP and five SZ‐eQTL genes for functional evaluation. By integrating CRISPR‐mediated gene editing, activation and repression technologies, our isogenic hiPSC‐based neuronal platform recapitulated genotype‐dependent gene expression differences from post‐mortem brains in SNP‐edited hiPSC‐neurons, identified evidence of molecular convergence downstream of common variant perturbations and uncovered specific pre‐ and post‐synaptic neuronal deficits associated with the SZ‐eQTL gene SNAP91 . We demonstrate a systematic and comprehensive strategy to interpret and evaluate the growing number of SZ‐associated variants and genes across neural cell types and genetic backgrounds, which will be applicable to other complex genetic disorders driven in large part by common variation. Ultimately, our objective is to understand the cell‐type specific contributions of SZ risk variants to disease predisposition. Support or Funding Information This work was partially supported by National Institute of Health (NIH) grants R01 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) and R01 MH109897 (P.S. and K.J.B.) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .