Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.
Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.
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DOI：
10.1016/s0140-6736(10)61109-9
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发表时间：
2010-10-23
期刊：
影响因子：
168.9
通讯作者：
Thapar, Anita
中科院分区：
文献类型：
--
作者：
Williams, Nigel M.;Zaharieva, Irina;Martin, Andrew;Langley, Kate;Mantripragada, Kiran;Fossdal, Ragnheidur;Stefansson, Hreinn;Stefansson, Karl;Magnusson, Pall;Gudmundsson, Olafur O.;Gustafsson, Omar;Holmans, Peter;Owen, Michael J.;O'Donovan, Michael;Thapar, Anita
被称为拷贝数变异（CNVs）的大而罕见的染色体缺失和重复与类似于注意力缺陷多动障碍（ADHD）的神经发育障碍有关。我们的目的是确定CNVs的负担是否在ADHD中增加，并调查已鉴定的CNVs是否富集于先前在自闭症和精神分裂症中鉴定的位点。我们对来自1958年英国出生队列的410名ADHD儿童和1156名不相关的种族匹配对照进行了全基因组的CNVs分析。从社区儿童精神病学和儿科门诊诊所招募了5-17岁的英国白人儿童，他们符合ADHD或多动障碍的诊断标准，但不包括精神分裂症和自闭症。对ADHD组和对照组进行单核苷酸多态性（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。通过比较基因组杂交验证ADHD组的CNVs。我们根据每个样本的平均CNVs数量评估了大（bb0 500 kb）、罕见（<1%种群频率）CNVs的全基因组负担，并通过排列评估了显著性。对所有已确定的CNVs和与自闭症或精神分裂症有关的20个基因座定义的测试区域进行了基因座特异性关联测试。研究结果在825名冰岛ADHD患者和35 243名冰岛对照组中得到了重复。对366名ADHD儿童和1047名对照组进行了全面分析。在ADHD儿童中发现了57个大的、罕见的CNVs，在对照组中发现了78个，表明ADHD儿童中CNVs的发生率显著增加（0.156 vs 0.075; p= 8.9×10−5）。这种增加的CNVs率在智力残疾者中特别高（0.424,p=2·0×10−6），尽管在没有智力残疾者中也有显著的增加（0.125,p= 0.0077）。在ADHD组中发现了过量的16p13.11染色体重复（经多次测试校正后p= 0.0008），这一发现在冰岛样本中也得到了重复（p= 0.031）。在我们的ADHD队列中发现的CNVs显著富集了之前在自闭症（p= 0.0095）和精神分裂症（p= 0.010）中报道的位点。我们的研究结果提供了遗传证据，证明ADHD患者的大CNVs率增加，并表明ADHD不纯粹是一种社会结构。行动研究;贝利托马斯慈善信托基金；威康信托基金会;联合王国医学研究理事会；欧盟。
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. 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. 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). 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. Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.