Synergistic effects of common schizophrenia risk variants.

Nature genetics (2019-09-25)
Nadine Schrode, Seok-Man Ho, Kazuhiko Yamamuro, Amanda Dobbyn, Laura Huckins, Marliette R Matos, Esther Cheng, P J Michael Deans, Erin Flaherty, Natalie Barretto, Aaron Topol, Khaled Alganem, Sonya Abadali, James Gregory, Emily Hoelzli, Hemali Phatnani, Vineeta Singh, Deeptha Girish, Bruce Aronow, Robert Mccullumsmith, Gabriel E Hoffman, Eli A Stahl, Hirofumi Morishita, Pamela Sklar, Kristen J Brennand
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Trizma® hydrochloride, BioPerformance Certified, suitable for cell culture, ≥99.0% (titration)
Sigma-Aldrich
N-Lauroylsarcosine sodium salt, detergent for use in cell lysis
Sigma-Aldrich
Anti-GABA antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution