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

Klaus Peter Lesch (1) , Christian Jacob (1) , Sandra Selch (1) , Monika Heine (1) , Andrea Boreatti-Hümmer (1) , Thomas Wultsch (1) , Andreas Reif (1) , Tobias Renner (1) , Marcel Romanos (1) , Susanne Walitza (1) , Andreas Warnke (1) , Martin Fassnacht (1) , Bruno Allolio (1) , T. Trang Nguyen (1) , Astrid Dempfle (1) , Heiko Zerlaut (1) , Helmut Schäfer (1) , Sarah Shoichet (1) , Hans-Hilger Ropers (1) , Reinhard Ullmann (1) , Tim Hahn (1) , Sebastian Heinzel (1) , Andreas J. Fallgatter (1)

1 Department of Psychiatry

Attention deficit / hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterised by hyperactivity, inattention, and increased impulsivity. To detect micro-deletions and -duplications which may play a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNV) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array Comparative Genomic Hybridisation (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise four deletions and thirteen 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-metabolising 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 alpha 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 FBAT, p = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses in duplication carriers elicited by fMRI links gene dose-dependent increases in NPY to reward and emotion processing. 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.

Mots clés: ADHD; copy number variation; deletion; duplication; neuropeptide Y

Klaus Peter Lesch, Christian Jacob, Sandra Selch, Monika Heine, Andrea Boreatti-Hümmer, et al.. Genome-wide copy number variation analysis in attention deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Molecular Psychiatry, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/mp.2010.29⟩. ⟨hal-00520360⟩