Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree
| Autor: | T. Trang Nguyen, Reinhard Ullmann, Hans-Hilger Ropers, M. Fassnacht, Tobias J. Renner, Andreas J. Fallgatter, Andrea Boreatti-Hümmer, Sebastian Heinzel, Christian Jacob, H. Zerlaut, Sarah A. Shoichet, Tim Hahn, Thomas Wultsch, Susanne Walitza, H. Schäfer, Monika Heine, S. Selch, Marcel Romanos, Andreas Reif, Astrid Dempfle, Jasmin Romanos, Bruno Allolio, Silke Gross-Lesch, K.P. Lesch, Andreas Warnke |
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| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2010 |
| Předmět: |
Male
Adolescent DNA Copy Number Variations 2804 Cellular and Molecular Neuroscience Gene Dosage 610 Medicine & health Biology Genetic determinism Cohort Studies 2738 Psychiatry and Mental Health Cellular and Molecular Neuroscience mental disorders Gene duplication 1312 Molecular Biology Image Processing Computer-Assisted medicine Humans Attention deficit hyperactivity disorder Neuropeptide Y Copy-number variation Child Molecular Biology Gene Family Health Genetics Comparative Genomic Hybridization Brain Chromosome Mapping 10058 Department of Child and Adolescent Psychiatry Neuropeptide Y receptor medicine.disease Magnetic Resonance Imaging Pedigree Oxygen Psychiatry and Mental health Phenotype Attention Deficit Disorder with Hyperactivity Anticipation (genetics) Female Chromosomes Human Pair 7 Genome-Wide Association Study Comparative genomic hybridization |
| Zdroj: | Molecular Psychiatry. 16:491-503 |
| ISSN: | 1476-5578 1359-4184 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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