Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders.
Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders.
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DOI：
10.1186/s11689-023-09483-z
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发表时间：
2023-04-29
影响因子：
4.9
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中科院分区：
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神经发育障碍（NDD），如注意缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD），是复杂和部分重叠的表型的例子，往往缺乏明确的确证遗传信息。ADHD和ASD具有复杂的遗传关联，涉及罕见的复发性拷贝数变异（CNVs）。这两种NDD已被证明具有相似的生物学病因以及遗传多效性。旨在研究基于遗传的关联的平台，如高密度微阵列技术，是复杂疾病领域的突破性技术，旨在阐明潜在的疾病生物学。以前的研究已经发现了与共享候选基因组网络中的基因相关的CNV，包括谷氨酸受体基因，跨越多个不同的NDD。为了研究两种最常见的NDD之间的共同生物学途径，我们研究了15，689名ADHD（n = 7920），ASD（n = 4318）或两者兼而有之（n = 3，416）个体以及19，993名对照者的CNV。病例和对照通过基因型阵列匹配（即，Illumina阵列版本）。三项病例对照关联研究分别计算并比较了个体基因、基因座、通路和基因网络中CNV的观察频率与预期频率。在关联分析之前，CNV-调用的置信度的质量控制措施包括基因型和杂交强度的目视检查。在这里，我们报告的结果CNV分析在寻找个别基因，基因座，途径和基因网络。为了扩展我们先前的观察结果，即代谢型谷氨酸受体（mGluR）网络在ADHD和自闭症中的关键作用，我们详尽地询问了ASD和/或ADHD患者与mGluR基因网络内273个感兴趣的基因组区域（与mGluR 1-8基因具有1或2度蛋白质-蛋白质相互作用的基因）相关的CNV。在mGluR网络基因的CNVs中，我们发现CNTN 4缺失在NDD病例中富集（P = 3.22E-26，OR = 2.49）。此外，我们发现40例ADHD病例和12例对照中存在PRLHR缺失（P = 5.26E-13，OR = 8.45）以及23例ADHD + ASD病例和9例对照中临床诊断相关的22q11.2重复和16p11.2重复在34例ADHD + ASD病例和51例对照中，22q11.2重复（P = 4.08E − 13，OR = 15.05）;这些对照样本在EHR记录中没有先前的22 qDS诊断。总之，这些结果表明，神经元细胞粘附途径的破坏赋予了NDD的显著风险，并显示CNTN 4，22q11.2和16p11.2中罕见的复发性CNV在NDD中的代表性过高，这些NDD构成了主要患有ADHD和ASD的患者。ClinicalTrials.gov 标识符：NCT 02286817首次发布日期：2014年11月10日，ClinicalTrials.gov标识符：NCT 02777931首次发布日期：2016年5月19日，ClinicalTrials.gov标识符：NCT 03006367首次发布日期：2016年12月30日，ClinicalTrials.gov标识符：NCT 02895906首次发布日期：2016年9月12日。在线版本包含补充材料，可通过10.1186/s11689-023-09483-z获得。
Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy. Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case–control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity. Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein–protein interaction with mGluR 1–8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E − 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E − 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E − 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E − 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records. Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD. ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016. The online version contains supplementary material available at 10.1186/s11689-023-09483-z.
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影响因子：
5.2
作者：
Glessner, Joseph T.;Li, Jin;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
DOI：
10.1002/ajmg.b.32253
发表时间：
2014-09-01
影响因子：
2.8
作者：
Akutagava-Martins, Glaucia Chiyoko;Salatino-Oliveira, Angelica;Hutz, Mara H.
通讯作者：
Hutz, Mara H.
影响因子：
14.9
作者：
Glessner JT;Li J;Hakonarson H
通讯作者：
Hakonarson H
影响因子：
1.3
作者：
Qi Q;Zhou X;Jiang Y;Hao N;Zhou J;Zhang L
通讯作者：
Zhang L
影响因子：
6.8
作者：
Régio Brambilla C;Veselinović T;Rajkumar R;Mauler J;Matusch A;Ruch A;Orth L;Ramkiran S;Sbaihat H;Kaulen N;Khudeish NY;Wyss C;Heekeren K;Kawohl W;Rota Kops E;Tellmann L;Scheins J;Boers F;Neumaier B;Ermert J;Lang M;Stüsgen S;Herzog H;Langen KJ;Shah NJ;Lerche CW;Neuner I
通讯作者：
Neuner I