Genotype-phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study
Genotype-phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study
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DOI：
10.1016/s2215-0366(19)30123-3
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发表时间：
2019-06-01
影响因子：
64.3
通讯作者：
van den Bree, Marianne B. M.
中科院分区：
文献类型：
--
作者：
Chawner, Samuel J. R. A.;Owen, Michael J.;van den Bree, Marianne B. M.
背景几种拷贝数变异（CNVs）与神经发育和精神疾病（简称ND-CNVs）的高风险相关。我们的目的是验证ND-CNVs对儿童发育的影响，并调查不同的ND-CNVs是否会导致不同的和特定的模式的认知和行为outcome.Methods在这个病例对照研究中，我们使用的数据从智力残疾和心理健康：评估基因组对神经发育的影响（IMAGINE-ID）研究。通过英国国家卫生服务体系（NHS）医学遗传诊所网络和患者支持小组招募了患有致病性CNV或单核苷酸变异的4岁及以上儿童，以完成广泛的在线表型分析，其中6-19岁的儿童至少患有一种特定ND-CNV组（1q21.1 [近端重复，远端缺失和重复]，2p16.3缺失，9q34.3缺失，15q11.2缺失，15q13.3缺失和重复，16p11.2 [近端缺失和重复，远端缺失]，和22q11.2缺失和重复）及其家庭进行了深入的表型分析，基于家庭的评估，我们在这里报告这个样本。我们邀请了索引儿童的兄弟姐妹作为对照组参与，通过使用微阵列结果以及可能的医疗记录排除ND-CNVs的存在。我们系统地评估了儿童的精神障碍和神经发育、认知和精神病理学起源的更广泛特征，并将ND-CNV携带者的结果与对照兄弟姐妹进行了比较，以检验表型因基因型而异的假设，无论是在严重程度方面的定量还是在相关损伤模式方面的定性。在招募的2819名儿童中，258名（9%）有一个感兴趣的ND-CNV，在9个位点上有13个CNV，并进行了基于家庭的评估。106名对照兄弟姐妹入组。186例（80%）ND-CNV携带者符合一种或多种精神疾病的标准（与对照组相比，比值比[OR] 13.8，95%CI 7.2-26.3）。与对照组相比，注意缺陷多动障碍（OR 6.9，3.2-15.1）、对立违抗性障碍（OR 3.6，1.4-9.4）、任何焦虑障碍（OR 2.9，1.2-6.7）和自闭症谱系障碍特征（OR 44.1，15.3-127.5）的风险特别高。与对照组相比，ND-CNV携带者的所有神经发育、认知和精神病理学特征均受损。基因型之间的表型谱仅存在中度的定量和定性差异。总体而言，所有ND-CNV基因型的表型范围大致相似。性状确实显示了一些基因型特异性的证据，基于等级的分析显示ND-CNVs之间存在中度的定性和定量差异;然而，特定的基因型在认知和行为结果的变异中所占的比例很低，（根据性状，大约5-20%）。解释所研究的13种ND-CNV对儿童神经发育具有类似范围的不利影响，尽管有细微的数量和质量差异。神经精神障碍的基因组风险对多个过程和神经回路具有多效性影响，并表明未来的研究应避免狭隘地集中在单一表型上。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Several copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (referred to as ND-CNVs). We aimed to characterise the effect of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes.Methods In this case-control study, we used data from the Intellectual Disability and Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study. Children aged 4 years and older with pathogenic CNV or single nucleotide variants were recruited via the UK National Health Service (NHS) medical genetic clinic network and via patient support groups to complete broad online phenotyping, from whom children aged 6-19 years with at least one of a specific group of ND-CNVs (1q21.1 [proximal duplication, and distal deletion and duplication], 2p16.3 deletion, 9q34.3 deletion, 15q11.2 deletion, 15q13.3 deletion and duplication, 16p11.2 [proximal deletion and duplication, and distal deletion], and 22q11.2 deletion and duplication) and their families were approached for a deep phenotyping, home-based assessment, and we report on this sample here. We invited siblings of index children to participate as controls, for whom the presence of ND-CNVs was excluded by use of microarray results and also medical records where possible. We systematically assessed the children for psychiatric disorders and broader traits of neurodevelopmental, cognitive, and psychopathological origin and compared results of ND-CNV carriers with control siblings to test the hypothesis that phenotypes would differ by genotype, both quantitatively in terms of severity and qualitatively in the pattern of associated impairments.Findings Between Oct 1, 2014, and Dec 31, 2018, of 2819 children recruited, 258 (9%) had one ND-CNV of interest, with 13 CNVs across nine loci, and underwent a home-based assessment. 106 control siblings were enrolled. 186 (80%) of ND-CNV carriers met criteria for one or more psychiatric disorder (odds ratio [OR] 13.8, 95% CI 7.2-26.3, compared with controls). The risk of attention-deficit hyperactivity disorder (OR 6.9, 3.2-15.1), oppositional defiant disorder (OR 3.6, 1.4-9.4), any anxiety disorder (OR 2.9, 1.2-6.7), and autism spectrum disorder traits (OR 44.1, 15.3-127.5) was particularly high compared with controls. ND-CNV carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits compared with controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. Overall, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, with rank-based analyses showing moderate qualitative and quantitative profile differences between ND-CNVs; however, the specific genotype accounted for a low proportion of variance in cognitive and behavioural outcomes (approximately 5-20% depending on the trait).Interpretation The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits and indicates that future research should avoid being narrowly focused on single phenotypes. Copyright (C) 2019 Elsevier Ltd. All rights reserved.