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
  • Animals
  • Attention Deficit Disorder with Hyperactivity*/genetics
  • Brain
  • Child
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Endosomal Sorting Complexes Required for Transport*
  • Gene Editing
  • Genome-Wide Association Study
  • Humans
  • Methylphenidate*
  • Zebrafish
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
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes