Jarick, I., Volckmar, A-L, Puetter, C., Pechlivanis, S., Nguyen, T. T., Dauvermann, M. R., Beck, S., Albayrak, Oe, Scherag, S., Gilsbach, S., Cichon, S., Hoffmann, P., Degenhardt, F., Noethen, M. M., Schreiber, S., Wichmann, H-E, Joeckel, K-H, Heinrich, J., Tiesler, C. M. T., Faraone, S. V., Walitza, S., Sinzig, J., Freitag, C., Meyer, J., Herpertz-Dahlmann, B., Lehmkuhl, G., Renner, T. J., Warnke, A., Romanos, M., Lesch, K-P, Reif, A., Schimmelmann, B. G., Hebebrand, J., Scherag, A. and Hinney, A. (2014). Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Mol. Psychiatr., 19 (1). S. 115 - 122. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5578

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Abstract

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 (> 500kb) 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 x 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 x 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 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Jarick, I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volckmar, A-LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puetter, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pechlivanis, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen, T. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dauvermann, M. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albayrak, OeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherag, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gilsbach, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cichon, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degenhardt, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, M. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreiber, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wichmann, H-EUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joeckel, K-HUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinrich, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tiesler, C. M. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faraone, S. V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walitza, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinzig, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freitag, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herpertz-Dahlmann, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehmkuhl, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renner, T. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warnke, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romanos, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesch, K-PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schimmelmann, B. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hebebrand, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherag, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hinney, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-452533
DOI: 10.1038/mp.2012.161
Journal or Publication Title: Mol. Psychiatr.
Volume: 19
Number: 1
Page Range: S. 115 - 122
Date: 2014
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5578
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DEFICIT HYPERACTIVITY DISORDER; RECURRENT MICRODELETIONS; MOLECULAR-GENETICS; ADHD; ASSOCIATION; VARIANTS; DISEASE; SCHIZOPHRENIA; DUPLICATIONS; AUTISMMultiple languages
Biochemistry & Molecular Biology; Neurosciences; PsychiatryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/45253

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