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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Acknowledgements
We thank the patients and their families for their participation and support. We greatly appreciate the input from co-workers, who contributed to organization of the study, data management and technical assistance: Annette Nowak, Gabriele Ortega, Nicole Steigerwald, Nicole Döring and Theresia Töpner. This study was supported by the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581, SFB TRR 58, GRK 1156, GRK 1253) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605).
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Author contributions: The study was conceptualized and supervised by KPL, AW, HHR and RU. MR, JR and CJ ascertained and clinically characterized the patients. SW, TR, MH, AB-H and CJ contributed to clinical characterization of family members. SS, SS and RU carried out the genetic analysis. KPL, SS, RU and TR evaluated the genomic data. MF and BA determined NPY plasma concentrations. TH, SH and AF conducted and analysed the fMRI. TW and AR contributed expertise on genetic analyses and NPY animal models. TN, AD, HZ, and HS performed statistical analyses. KPL, TR, SS, AR and RU wrote and revised the paper.
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Lesch, KP., Selch, S., Renner, T. et al. Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Mol Psychiatry 16, 491–503 (2011). https://doi.org/10.1038/mp.2010.29
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DOI: https://doi.org/10.1038/mp.2010.29
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