Synergistic Effects of Common Schizophrenia Risk Variants

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Sep 25

PMID 31548722

Citations 121

Authors

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

Affiliations

Soon will be listed here.

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.

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