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  Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree1

Lesch, K.-P., Selch, S., Renner, T. J., Jacob, C., Nguyen, T. T., Hahn, T., et al. (2010). Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree1. Molecular Psychiatry, 1-13. doi:10.1038/mp.2010.29.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7B8F-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7B90-1
Genre: Journal Article
Alternative Title : Mol. Psychiatry

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 Creators:
Lesch, K.-P., Author
Selch, S., Author
Renner, T. J., Author
Jacob, C., Author
Nguyen, T. T., Author
Hahn, T., Author
Romanos, M., Author
Walitza, S., Author
Shoichet, S.1, Author
Dempfle, A., Author
Heine, M., Author
Boreatti-Hümmer, A., Author
Romanos, J., Author
Gross-Lesch, S., Author
Zerlaut, H., Author
Wultsch, T., Author
Heinzel, S., Author
Fassnacht, M., Author
Fallgatter, A., Author
Allolio, B., Author
Schäfer, H.1, AuthorA Warnke, A., AuthorReif, A ., AuthorRopers, Hans-Hilger2, Author              Ullmann, Reinhard3, Author               more..
Affiliations:
1Max Planck Society, ou_persistent13              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
3Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              

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Free keywords: ADHD; copy number variation; duplication; neuropeptide Y; BCHE; SLC2A3
 Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domain-containing protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 α subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a ~3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P=0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

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Language(s): eng - English
 Dates: 2010-03-23
 Publication Status: Published in print
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Title: Molecular Psychiatry
  Alternative Title : Mol. Psychiatry
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: - Start / End Page: 1 - 13 Identifier: ISSN: 1359-4184