Synergistic effects of common schizophrenia risk variants

• Published in: Nature genetics Vol. 51; no. 10; pp. 1475 - 1485
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2019
• Subjects: Autism; Bioinformatics; Care and treatment; Chloride Channels - antagonists & inhibitors; Chloride Channels - genetics; Chloride Channels - metabolism; Consortia; Convergence; CRISPR; CRISPR-Cas Systems; Disorders; Female; Furin; Furin - antagonists & inhibitors; Furin - genetics; Furin - metabolism; Gene Editing; Gene expression; Gene Expression Regulation; Gene mapping; Genes; Genetic aspects; Genetic disorders; Genetic engineering; Genetic modification; Genetic Predisposition to Disease; Genome editing; Genome-Wide Association Study; Genomes; Genomics; Genotypes; Health risks; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Male; Mental disorders; Monomeric Clathrin Assembly Proteins - antagonists & inhibitors; Monomeric Clathrin Assembly Proteins - genetics; Monomeric Clathrin Assembly Proteins - metabolism; Neurons; Pluripotency; Polymorphism, Single Nucleotide; Proteins; Quantitative Trait Loci; Risk; Risk factors; Schizophrenia; Schizophrenia - genetics; Schizophrenia - pathology; SNARE Proteins - antagonists & inhibitors; SNARE Proteins - genetics; SNARE Proteins - metabolism; Stem cells; Synergistic effect
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0497-5

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.