PUBLICATION

Functional validation of CHMP7 as an ADHD risk gene

Authors
Dark, C., Williams, C., Bellgrove, M.A., Hawi, Z., Bryson-Richardson, R.J.
ID
ZDB-PUB-201120-62
Date
2020
Source
Translational psychiatry   10: 385 (Journal)
Registered Authors
Bryson-Richardson, Robert, Dark, Callum
Keywords
none
MeSH Terms
  • Zebrafish
  • Humans
  • Child
  • Gene Editing
  • Genome-Wide Association Study
  • Endosomal Sorting Complexes Required for Transport*
  • Brain
  • Methylphenidate*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Animals
  • Attention Deficit Disorder with Hyperactivity*/genetics
(all 11)
PubMed
33159045 Full text @ Transl Psychiatry
Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7+/- fish showed comparable reductions in mRNA levels to individuals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7+/+, but this effect did not persist into juvenile and adulthood stages. In addition, chmp7+/- fish had significantly smaller total brain volumes than chmp7+/+ fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.
Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
chmp7mnu7/+ (TU)standard conditionsDay 6
chmp7mnu7/+ (TU)standard conditionsDay 6 to Days 7-13
chmp7mnu7/+ (TU)standard conditionsDays 30-44
chmp7mnu7/+ (TU)standard conditionsDays 45-89
chmp7mnu7/+; knu3TgcontrolDay 6 to Days 7-13
chmp7mnu7/+; knu3Tgstandard conditionsDay 6
chmp7mnu7/+; knu3Tgchemical treatment by environment: methylphenidateDay 6 to Days 7-13
chmp7mnu7/mnu7 (TU)standard conditionsDay 6
1 - 8 of 8
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
knu3TgTransgenic Insertion
    mnu7
      		Small Deletion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      attention deficit hyperactivity disorderTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      Fish
      Antibodies
      Orthology
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
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      Citation
      Dark, C., Williams, C., Bellgrove, M.A., Hawi, Z., Bryson-Richardson, R.J. (2020) Functional validation of CHMP7 as an ADHD risk gene. Translational psychiatry. 10:385.