注意缺陷多动障碍中的罕见染色体缺失和重复：全基因组分析。

Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.

机构信息

MRC Centre in Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Cardiff, UK.

出版信息

Lancet. 2010 Oct 23;376(9750):1401-8. doi: 10.1016/S0140-6736(10)61109-9. Epub 2010 Sep 29.

DOI:10.1016/S0140-6736(10)61109-9

PMID:20888040

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2965350/

Abstract

BACKGROUND

Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia.

METHODS

We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls.

FINDINGS

Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10(-5)). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10(-6)), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010).

INTERPRETATION

Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct.

FUNDING

Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.

摘要

背景

被称为拷贝数变异（CNVs）的大型罕见染色体缺失和重复与类似注意缺陷多动障碍（ADHD）的神经发育障碍有关。我们旨在确定 ADHD 中是否存在 CNV 负担增加，并调查鉴定出的 CNV 是否富集了先前在自闭症和精神分裂症中发现的基因座。

方法

我们对来自 1958 年英国出生队列的 410 名 ADHD 儿童和 1156 名无关的、种族匹配的对照进行了全基因组 CNV 分析。招募了来自社区儿童精神病学和儿科门诊的符合 ADHD 或多动障碍诊断标准的白人英国血统儿童，年龄 5-17 岁，但不包括精神分裂症和自闭症患者。在 ADHD 和对照组中，使用两种阵列进行了单核苷酸多态性（SNP）基因分型；CNV 分析仅限于两种阵列共有的 SNP，并且仅包括具有高质量数据的样本。使用比较基因组杂交对 ADHD 组中的 CNV 进行了验证。我们根据每个样本的 CNV 数量评估了大（>500kb）、罕见（<1%人群频率）CNV 的全基因组负担，并通过置换检验评估了显著性。对所有鉴定出的 CNV 以及 20 个与自闭症或精神分裂症相关的基因座进行了特定区域的关联测试。在 825 名冰岛 ADHD 患者和 35243 名冰岛对照中进行了复制。

发现

366 名 ADHD 儿童和 1047 名对照的全分析数据可用。在 ADHD 儿童中发现了 57 个大型罕见 CNV，在对照组中发现了 78 个，ADHD 中 CNV 的发生率显著增加（0.156 比 0.075；p=8.9×10(-5)）。在智力障碍者中，这种 CNV 的发生率尤其高（0.424；p=2.0×10(-6)），尽管在没有这种残疾的病例中也存在显著的过度（0.125，p=0.0077）。ADHD 组中注意缺陷多动障碍 16p13.11 重复过度（经多次测试校正后 p=0.0008），这一发现在冰岛样本中得到了复制（p=0.031）。我们 ADHD 队列中鉴定出的 CNV 显著富集了先前在自闭症（p=0.0095）和精神分裂症（p=0.010）中报道的基因座。