학술논문
Synergistic effects of common schizophrenia risk variants
Document Type
Report
Author
Source
Nature Genetics. October 2019, Vol. 51 Issue 10, p1475, 11 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Author(s): Nadine Schrode [sup.1] [sup.2] , Seok-Man Ho [sup.3] [sup.4] , Kazuhiko Yamamuro [sup.5] [sup.6] , Amanda Dobbyn [sup.1] [sup.2] , Laura Huckins [sup.1] [sup.2] [sup.7] , Marliette R. Matos [...]
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, TSNARE1andCLCN3), 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. Combinatorial perturbation of schizophrenia risk loci in human induced pluripotent stem cell-derived neuronal cells demonstrates a synergistic effect converging on synaptic function.
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, TSNARE1andCLCN3), 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. Combinatorial perturbation of schizophrenia risk loci in human induced pluripotent stem cell-derived neuronal cells demonstrates a synergistic effect converging on synaptic function.