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Nat Genet. 2019 Oct;51(10):1475-1485. doi: 10.1038/s41588-019-0497-5. Epub 2019 Sep 23.

Synergistic effects of common schizophrenia risk variants.

Author information

1
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Department of Stem Cell and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Department of Neurosciences, Institute in the College of Medicine & Life Sciences, The University of Toledo, Toledo, OH, USA.
10
Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY, USA.
11
UC Department of Pediatrics Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
13
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
14
Department of Stem Cell and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
15
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
16
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
17
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.
18
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kristen.brennand@mssm.edu.

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.

PMID:
31548722
PMCID:
PMC6778520
[Available on 2020-03-23]
DOI:
10.1038/s41588-019-0497-5

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