Using hiPSC-derived neural cells, we set out to systemically test the ability of different gRNAs targeting the presumptive promoter regions of five different SZ-associated risk genes: potassium channel tetramerization domain containing 13 (KCTD13) and thousand and one amino acid protein kinase 2 (TOAK2) resides within 16p11.2, and neurexin 1 (NRXN1) within 2p16.3, two loci where recurrent CNVs are associated with intellectual disability, autism spectrum disorder, SZ, and other neuropsychiatric disorders (CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium and Psychosis Endophenotypes International Consortium, 2017, Maillard et al., 2015), whereas synaptosome-associated protein 91 (SNAP91) and chloride voltage-gated channel 3 (CLCN3) have both recently been implicated with SZ risk via cis-eQTLs genome-wide association study variant analysis (Fromer et al., 2016). By evaluating dCas9-mediated transcriptional modulation using three different platforms (downregulation using a dCas9 fusion to the Krüppel-associated box [KRAB] repressor domain [Thakore et al., 2015]; upregulation using a dCas9 fusion to the tetrameric VP16 transcription activator domain [VP64] [Kearns et al., 2014, Maeder et al., 2013] or the tripartite activator, VP64-p65-Rta (VPR) [Chavez et al., 2015, Chavez et al., 2016]),
