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Schrode, Nadine; Ho, Seok-Man; Yamamuro, Kazuhiko; Dobbyn, Amanda; Huckins, Laura; Matos, Marliette R; Cheng, Esther; Deans, P J Michael; Flaherty, Erin; Barretto, Natalie; Topol, Aaron; Alganem, Khaled; Abadali, Sonya; Gregory, James; Hoelzli, Emily; Phatnani, Hemali; Singh, Vineeta; Girish, Deeptha; Aronow, Bruce; Mccullumsmith, Robert; Hoffman, Gabriel E; Stahl, Eli A; Morishita, Hirofumi; Sklar, Pamela; Brennand, Kristen J
Nature genetics, 10/2019, Volume: 51, Issue: 10Journal Article
The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders are unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells, to evaluate the effects of schizophrenia (SZ)-associated common variants predicted to function as SZ expression quantitative trait loci (eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ eQTL (FURIN rs4702) and four top-ranked SZ eQTL genes (FURIN, SNAP91, TSNARE1 and CLCN3), our platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.
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