PUBLICATION

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

Authors
Thyme, S.B., Pieper, L.M., Li, E.H., Pandey, S., Wang, Y., Morris, N.S., Sha, C., Choi, J.W., Herrera, K.J., Soucy, E.R., Zimmerman, S., Randlett, O., Greenwood, J., McCarroll, S.A., Schier, A.F.
ID
ZDB-PUB-190402-7
Date
2019
Source
Cell   177(2): 478-491.e20 (Journal)
Registered Authors
Schier, Alexander, Thyme, Summer, Zimmerman, Steve
Keywords
GWAS, behavior, forebrain, neurodevelopment, neuropsychiatric disorder, prepulse inhibition, schizophrenia, single-cell RNA-sequencing, whole-brain activity, zebrafish
Datasets
GEO:GSE115427
MeSH Terms
  • Polymorphism, Single Nucleotide/genetics
  • Animals
  • Brain
  • Zebrafish/genetics
  • Cerebral Cortex
  • Gene Expression Regulation/genetics
  • Phenotype
  • Genetic Predisposition to Disease
  • Disease Models, Animal
  • Schizophrenia/genetics*
  • Schizophrenia/physiopathology*
  • Genome-Wide Association Study
(all 12)
PubMed
30929901 Full text @ Cell
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.
Genes / Markers
Figures
Figure Gallery (8 images)
Show all Figures
Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3aa229/a229standard conditionsDay 4
akt3ba230/a230standard conditionsDay 4
akt3ba230/a230standard conditionsDay 4
akt3ba230/a230standard conditionsDay 4
1 - 10 of 683
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a211
    		Complex
    a212
      		Indel
      a213
        		Small Deletion
        a214
          		Small Deletion
          a215
            		Complex
            a216
              		Small Deletion
              a217
                		Complex
                a218
                  		Complex
                  a219
                    		Complex
                    a220
                      		Complex
                      1 - 10 of 167
                      Show
                      Human Disease / Model
                      Human Disease Fish Conditions Evidence
                      schizophreniadre-mir-137-1a368/a368standard conditionsTAS
                      schizophreniacnnm2ba258/a258standard conditionsTAS
                      schizophreniaelfn1aa216/a216standard conditionsTAS
                      schizophreniaelfn1ba217/a217standard conditionsTAS
                      schizophreniasbno1a214/a214standard conditionsTAS
                      schizophreniaman2a2a298/a298standard conditionsTAS
                      schizophreniacsmd3aa254/a254standard conditionsTAS
                      schizophreniaakt3aa229/a229standard conditionsTAS
                      schizophreniashmt2a329/a329standard conditionsTAS
                      schizophrenialrrn3ba294/a294standard conditionsTAS
                      1 - 10 of 16
                      Show
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      adamtsl3CRISPR1-adamtsl3CRISPR
                      adamtsl3CRISPR2-adamtsl3CRISPR
                      adamtsl3CRISPR3-adamtsl3CRISPR
                      akt3aCRISPR1-akt3aCRISPR
                      akt3aCRISPR2-akt3aCRISPR
                      akt3aCRISPR3-akt3aCRISPR
                      akt3aCRISPR4-akt3aCRISPR
                      akt3bCRISPR2-akt3bCRISPR
                      akt3bCRISPR3-akt3bCRISPR
                      akt3bCRISPR4-akt3bCRISPR
                      1 - 10 of 534
                      Show
                      Fish
                      Fish
                      akt3aa229/a229
                      akt3ba230/a230
                      ambra1aa223/a223
                      ambra1ba224/a224
                      anp32ea231/a231
                      arhgap1a232/a232
                      astn1a235/a235
                      atxn7a236/a236
                      bcl11baa238/a238
                      bcl11bba239/a239
                      1 - 10 of 92
                      Show
                      Antibodies
                      No data available
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      GCaMPEFGGCaMP
                      1 - 1 of 1
                      Show
                      Mapping
                      No data available
                      Your Input Welcome
                      We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
                      Citation
                      Thyme, S.B., Pieper, L.M., Li, E.H., Pandey, S., Wang, Y., Morris, N.S., Sha, C., Choi, J.W., Herrera, K.J., Soucy, E.R., Zimmerman, S., Randlett, O., Greenwood, J., McCarroll, S.A., Schier, A.F. (2019) Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions. Cell. 177(2):478-491.e20.