Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions

Summer B Thyme; Lindsey M Pieper; Eric H Li; Shristi Pandey; Yiqun Wang; Nathan S Morris; Carrie Sha; Joo Won Choi; Kristian J Herrera; Edward R Soucy; Steve Zimmerman; Owen Randlett; Joel Greenwood; Steven A McCarroll; Alexander F Schier

doi:10.1016/j.cell.2019.01.048

Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions

Cell. 2019 Apr 4;177(2):478-491.e20. doi: 10.1016/j.cell.2019.01.048. Epub 2019 Mar 28.

Authors

Affiliations

¹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: sthyme@gmail.com.
² Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
³ Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.
⁵ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Center for Brain Science, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Biozentrum, University of Basel, CH-4056 Basel, Switzerland; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; FAS Center for Systems Biology, Harvard University, MA 02138, USA; Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98104, USA. Electronic address: schier@fas.harvard.edu.

Abstract

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.

Keywords: GWAS; behavior; forebrain; neurodevelopment; neuropsychiatric disorder; prepulse inhibition; schizophrenia; single-cell RNA-sequencing; whole-brain activity; zebrafish.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain
Cerebral Cortex
Disease Models, Animal
Gene Expression Regulation / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Phenotype
Polymorphism, Single Nucleotide / genetics
Schizophrenia / genetics*
Schizophrenia / physiopathology*
Zebrafish / genetics

Abstract

Publication types

MeSH terms

Grants and funding