Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study
Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study
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拷贝数变异与高神经精神风险相关的儿童的基因型-表型关系：来自智力障碍的发现
DOI：
10.1101/535708
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Chawner S
中科院分区：
文献类型：
--
作者：
Chawner S
背景多种拷贝数变异与神经发育和精神疾病（ND-CNVs）的高风险相关。不同的ND-CNVs可能导致不同的和特定的模式的认知和行为的结果，但目前缺乏支持证据。方法258名儿童ND-CNVs（13个CNVs在9个位点）进行了系统的评估精神疾病以及更广泛的特征的神经发育，认知和精神病理学的起源。与106名非携带者对照组的同胞进行比较，以检验以下假设，即不同基因型的表型在严重程度上存在定量差异，在相关损害模式上存在定性差异。结果79.8%的ND-CNVs携带者符合一种或多种精神疾病的标准（与对照组相比，OR=13.8）：ADHD（OR=6.9），ODD（OR=3.6），焦虑症（OR=2.9）和ASD特征（OR=44.1）的风险特别高。相对于对照组，ND-CNVs携带者的所有神经发育、认知和精神病理学特征均受损。只有中度的数量和质量的差异，在表型的基因型之间。一般而言，所有ND-CNV基因型的表型范围大致相似。性状确实显示出基因型特异性的一些证据，然而，特定基因型占结果方差的低比例（5-20%，取决于性状）。我们的研究结果表明，神经精神疾病的基因组风险具有多效性的影响，多个过程和神经回路，并提供了重要的影响，研究到基因型-表型的关系在精神病学。FundingThe医学研究理事会和医学研究基金会的研究在上下文的证据在这项研究之前，几个拷贝数变异（CNVs）已与儿童和成人神经精神疾病的发展的高风险。越来越多的发育迟缓儿童被诊断患有神经发育和精神病风险CNVs（以下称为ND-CNVs）。目前尚不清楚不同的基因型是否与特定的认知和行为表型相关，或者这些结果是否是非特异性的。我们在PubMed中搜索了从数据库建立到2019年1月10日发表的研究，这些研究调查了CNV与认知和行为结果之间的关系。检索词包括“CNV”、“基因组学”、“1q21.1”、“2p16.3”、“NRXN 1”、“9 q34”、“Kleefstra综合征”、“15q11.2”、“15q13.3”、“16p11.2”、“22q11.2”、“精神病学”和“认知”。初步研究表明，在同一基因座的缺失和重复可能会在认知和行为表型上有所不同。然而，到目前为止，已经有有限的研究，对比了ND-CNV的表型在几个位点上的一系列认知和行为domains.Added值这项研究我们发现，携带ND-CNV的年轻人在相当大的风险增加神经精神障碍和障碍的范围内的神经发育，精神病理学，认知，社会，睡眠和运动性状。在ND-CNV携带者中，基因型之间的比较表明总体表型特征存在中度定量和定性差异，有证据表明所有基因型的某些特征（例如情绪问题，睡眠障碍，同伴问题和持续注意力问题）的损害严重程度相似。
BackgroundA variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking.Methods258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments.Outcomes79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait).InterpretationThe 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry.FundingThe Medical Research Council and the Medical Research FoundationResearch in contextEvidence before this studySeveral copy number variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included “CNV”, “genomics”, “1q21.1”, “2p16.3”, “NRXN1”, “9q34”, “Kleefstra Syndrome”, “15q11.2”, “15q13.3”, “16p11.2”, “22q11.2”, “psychiatry”, and “cognition”. Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains.Added value of this studyWe found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention …
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影响因子：
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作者：
D. Shaffer;M. Gould;James Robert Brašić;P. Ambrosini;P. Fisher;H. Bird;S. Aluwahlia
通讯作者：
D. Shaffer;M. Gould;James Robert Brašić;P. Ambrosini;P. Fisher;H. Bird;S. Aluwahlia
影响因子：
10.5
作者：
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通讯作者：
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影响因子：
9.8
作者：
Miller, David T.;Adam, Margaret P.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.
DOI：
10.1176/appi.ajp.2017.16101115
发表时间：
2017-06-01
期刊：
The American journal of psychiatry
影响因子：
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作者：
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通讯作者：
Thurm A
影响因子：
10.6
作者：
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通讯作者：
Kirov, George