Site maintenance Wednesday, November 13th, 2024. Please note that access to some content and account information will be unavailable on this date.
Skip to main content

Abstract

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.

Formats available

You can view the full content in the following formats:

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 526 - 536
PubMed: 32046534

History

Received: 24 May 2018
Revision received: 10 May 2019
Revision received: 5 August 2019
Revision received: 17 October 2019
Accepted: 28 October 2019
Published online: 12 February 2020
Published in print: June 01, 2020

Keywords

  1. Intellectual Disability
  2. ADHD
  3. Genetics
  4. Drosophila melanogaster
  5. MEF2C
  6. TRAPPC9

Authors

Details

Marieke Klein, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Euginia L. Singgih, B.Sc.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Anne van Rens, M.Sc.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Ditte Demontis, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Anders D. Børglum, M.D., Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Nina Roth Mota, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Anna Castells-Nobau, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Lambertus A. Kiemeney, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Han G. Brunner, M.D., Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Alejandro Arias-Vasquez, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Annette Schenck, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Monique van der Voet, Ph.D.
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).
Barbara Franke, Ph.D. [email protected]
Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).

Notes

Send correspondence to Dr. Franke ([email protected]).
Presented in part at the IMpACT meeting, November 19–22, 2015, Florianopolis, Brazil; the Symposium of the Dutch Society for Human Genetics, October 22–23, 2015, Arnhem, the Netherlands; the 23rd World Congress of Psychiatric Genetics, October 16–20, 2015, Toronto; and the European Society of Human Genetics Conference, June 6–9, 2015, Glasgow.

Competing Interests

Dr. Børglum has received funding from the Lundbeck Foundation. Dr. Franke has received educational speaking fees from Shire and Medice. The other authors report no financial relationships with commercial interests.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Full Text

View Full Text

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share