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

Academic Article

Abstract

  • © 2019 Elsevier Inc. 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. Analysis of zebrafish deficient for human schizophrenia-associated genes generates an atlas of brain and behavior phenotypes for the study of psychiatric disorders.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Thyme SB; Pieper LM; Li EH; Pandey S; Wang Y; Morris NS; Sha C; Choi JW; Herrera KJ; Soucy ER
  • Start Page

  • 478
  • End Page

  • 491.e20
  • Volume

  • 177
  • Issue

  • 2