Contribution of Intellectual Disability-Related Genes to ADHD Risk and to Locomotor Activity in Drosophila

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Marieke Klein, Radboud University Medical Center
  • ,
  • Euginia L. Singgih, Radboud University Medical Center
  • ,
  • Anne van Rens, Radboud University Medical Center
  • ,
  • Ditte Demontis
  • Anders D. Børglum
  • Nina Roth Mota, Radboud University Medical Center
  • ,
  • Anna Castells-Nobau, Radboud University Medical Center
  • ,
  • Lambertus A. Kiemeney, Radboud University Medical Center
  • ,
  • Han G. Brunner, Radboud University Medical Center
  • ,
  • Alejandro Arias-Vasquez, Radboud University Medical Center
  • ,
  • Annette Schenck, Radboud University Medical Center
  • ,
  • Monique van der Voet, Radboud University Medical Center
  • ,
  • Barbara Franke, Radboud University Medical Center

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster. METHODS: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. RESULTS: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. CONCLUSIONS: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.

Original languageEnglish
JournalThe American Journal of Psychiatry
Volume177
Issue6
Pages (from-to)526-536
Number of pages11
ISSN0002-953X
DOIs
Publication statusPublished - Jun 2020

    Research areas

  • ADHD, Drosophila melanogaster, Genetics, Intellectual Disability, MEF2C, TRAPPC9

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