Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs),
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
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Metadaten
Author:Ivonne Jarick, Anna-Lena Volckmar, Carolin Pütter, Sonali Pechlivanis, Trang T. Nguyen, Maria R. Dauvermann, Sebastian Beck, Özgür Albayrak, Susann Scherag, Susanne Gilsbach, Sven Cichon, Per Hoffmann, Franziska Degenhardt, Markus Maria Nöthen, Stefan Schreiber, Heinz Erich Wichmann, Karl-Heinz Jöckel, Joachim Heinrich, Carla Marie Thérèse Tiesler, Stephen V. Faraone, Susanne Walitza, Judith Sinzig, Christine M. Freitag, Jobst Meyer, Beate Herpertz-Dahlmann, Gerd Lehmkuh, Tobias J. Renner, Andreas Warnke, Marcel Romanos, Klaus-Peter Lesch, Andreas Reif, Benno G. Schimmelmann, Johannes Hebebrand, André Scherag, Anke Hinney
URN:urn:nbn:de:hebis:30:3-372560
DOI:http://dx.doi.org/10.1038/mp.2012.161
ISSN:1476-5578
ISSN:1359-4184
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=23164820
Parent Title (English):Molecular psychiatry
Publisher:Macmillan
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2015/03/28
Year of first Publication:2012
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/03/28
Tag:PARK2
ADHD; CNVs; GWAS; children
Volume:19
Issue:1
Pagenumber:7
First Page:115
Last Page:121
Note:
Copyright © 2014 Macmillan Publishers Limited This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
HeBIS PPN:369077792
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0

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