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Published Online: 30 June 2020

From Rare Copy Number Variants to Biological Processes in ADHD

Benjamin Harich, M.Sc., Monique van der Voet, Ph.D., Marieke Klein, Ph.D., Pavel Čížek, M.Sc., Michaela Fenckova, Ph.D., Annette Schenck, Ph.D. [email protected], and Barbara Franke, Ph.D. [email protected]Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 177, Number 9
https://doi.org/10.1176/appi.ajp.2020.19090923
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Abstract

Objective:

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.

Methods:

The authors combined data from 11 published copy number variation studies in 6,176 individuals with ADHD and 25,026 control subjects and prioritized genes by applying an integrative strategy based on criteria including recurrence in individuals with ADHD, absence in control subjects, complete coverage in copy number gains, and presence in the minimal region common to overlapping copy number variants (CNVs), as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.

Results:

The authors localized 2,241 eligible genes in the 1,532 reported CNVs, of which they classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly coexpressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. Four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Lookup in the latest genome-wide association study for ADHD showed that among those 26 genes, POLR3C and RBFOX1 were also supported by common genetic variants.

Conclusions:

Integration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. The authors’ analytic pipeline provides additional insight into the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

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Supplementary Material

File (appi.ajp.2020.19090923.ds001.pdf)
File (appi.ajp.2020.19090923.ds002.xlsx)
File (appi.ajp.2020.19090923.ds002_tables2.xlsx)
File (appi.ajp.2020.19090923.ds003.xlsx)
File (appi.ajp.2020.19090923.ds003_tables5.xlsx)
File (appi.ajp.2020.19090923.ds004.xlsx)
File (appi.ajp.2020.19090923.ds004_tables6.xlsx)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 177 • Number 9 • September 01, 2020
Pages: 855 - 866
PubMed: 32600152

History

Received: 8 September 2019
Revision received: 8 March 2020
Accepted: 9 April 2020
Published online: 30 June 2020
Published in print: September 01, 2020

Keywords

  1. Attention Deficit Hyperactivity Disorder
  2. Genetics
  3. Copy Number Variants
  4. Cross-Species Phenotype
  5. Integrated Analysis

Authors

Affiliations

Benjamin Harich, M.Sc.
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Monique van der Voet, Ph.D.
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Marieke Klein, Ph.D.
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Pavel Čížek, M.Sc.
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Michaela Fenckova, Ph.D.
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Annette Schenck, Ph.D. [email protected]
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Barbara Franke, Ph.D. [email protected]
Department of Human Genetics (Harich, van der Voet, Klein, Fenckova, Schenck, Franke) and Department of Psychiatry (Franke), Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; and Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands (Čížek).
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Notes

Send correspondence to Dr. Schenck ([email protected]) and Dr. Franke ([email protected]).

Author Contributions

The first two authors contributed equally to this work.

Competing Interests

Dr. Franke has received educational speaking fees from Medice. The other authors report no financial relationships with commercial interests.

Funding Information

Mr. Harich was funded by a Radboud University Medical Center Ph.D. grant. Dr. van der Voet’s research was supported by the Netherlands Organization for Scientific Research (NWO) VENI grant (grant 91.614.084). Dr. Klein was supported by a grant from the Netherlands Science Agenda for the NeuroLabNL project (grant 400.17.602). Dr. Franke’s contribution was supported by a personal Vici grant from the NWO (grant 016-130-669). This work also received support from the European Community’s Horizon 2020 (H2020/2014–2020) European training network program “MiND” under grant agreement 643051 to Dr. Franke and Dr. Schenck. Additional support was received from the European College of Neuropsychopharmacology Network ADHD Across the Lifespan and the European Community’s Horizon 2020 Programme under grant agreements 667302 (CoCA) and 728018 (Eat2beNICE).

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