Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree
Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree
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DOI：
10.1038/mp.2010.29
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发表时间：
2011-05-01
影响因子：
11
通讯作者：
Ullmann, R.
中科院分区：
文献类型：
--
作者：
Lesch, K-P;Selch, S.;Ullmann, R.
注意缺陷/多动障碍（ADHD）是一种常见的、高度遗传性的神经发育综合征，其特征是多动、注意力不集中和冲动增加。为了检测可能在ADHD发病机制中起作用的微缺失和微重复，我们对99名患有严重ADHD的儿童和青少年进行了全基因组拷贝数变异（CNVs）筛查。使用高分辨率阵列比较基因组杂交（aCGH），共鉴定出17个潜在的综合征相关CNVs。畸变包括4个缺失和13个重复，大小约为110 kb至3 Mb。2个CNVs是从头发生的，9个遗传自患有ADHD的父母，而5个遗传自未受影响的父母。候选基因包括表达乙酰胆碱代谢丁基胆碱酯酶（BCHE）的基因，包含在一条新生染色体3q26.1缺失中，以及在两个携带11q13.4重复遗传自受影响母亲的兄弟姐妹中，在初级感觉神经元中具有既定功能的脑特异性pleckstrin同源结构域蛋白（PLEKHB1）。其他可能影响adhd相关精神病理和涉及从受影响父母遗传的畸变的基因是线粒体NADH脱氢酶1 a亚复合物组装因子2 （NDUFAF2）、脑特异性磷酸二酯酶4D异构体6 （PDE4D6）和神经元葡萄糖转运蛋白3 （SLC2A3）的基因。编码神经肽Y （NPY）的基因与7p15.2-15.3染色体上的3Mb重复相似，对其他家族成员的调查显示，7p15重复与NPY血浆浓度升高有名义上的显著关联（基于经验家族的关联检验，P = 0.023）。在功能性磁共振成像引发的对大奖励或大损失的预期中，左侧腹侧纹状体和左侧后岛的激活较低，将基因剂量依赖性的NPY增加与重复携带者的奖励和情绪处理联系起来。这些发现暗示了ADHD发病机制中行为相关基因的CNVs，并与常见和罕见变异影响这种常见多因素综合征发展的观点一致。分子精神病学（2011）16,491-503；doi: 10.1038 / mp.2010.29;2010年3月23日在线发布
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 a 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 similar to 3Mb 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. Molecular Psychiatry (2011) 16, 491-503; doi: 10.1038/mp.2010.29; published online 23 March 2010