An integrative approach to linking genes, brain, and behavior in 22q11.2 CNV's

连接 22q11.2 CNV 中的基因、大脑和行为的综合方法

• 批准号: 9759710
• 负责人: Amy Lin
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759710
• 关键词: 22q; 22q11.2; Affect; Area; Behavior; Behavioral; Biological; Biological Markers; Brain; Clinical; Cognition; Cognitive; Comorbidity; Complex; Copy Number Polymorphism; DNA; Development; Developmental Process; DiGeorge Syndrome; Disease; Evolution; Exhibits; Functional disorder; Gene Dosage; Gene Expression; General Population; Genes; Genetic; Genetic Risk; Glutamates; Goals; Heterogeneity; Immune; Individual; Intellectual functioning disability; Intervention; Link; Live Birth; Measures; Medical; Mental disorders; Modeling; Mutation; Neuronal Differentiation; Online Mendelian Inheritance In Man; Pathogenesis; Pathway interactions; Pattern; Phenotype; Population Study; Prevalence; Psychotic Disorders; Recurrence; Risk; Risk Factors; Schizophrenia; Shprintzen syndrome; Specificity; Structure; Surface; Symptoms; Thick; Variant; Youth; autism spectrum disorder; base; behavior measurement; brain behavior; brain dysfunction; cognitive ability; cognitive development; cohort; conotruncal anomaly face syndrome; developmental disease; differential expression; disorder risk; genetic variant; genomic variation; high risk; immune function; insight; migration; multimodality; neuron development; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; preservation; prospective; protective factors; psychotic symptoms; social cognition; specific language impairment; symptomatology; transcriptome

PROJECT SUMMARY / ABSTRACT A primary challenge in uncovering biological mechanisms of developmental neuropsychiatric illnesses like schizophrenia (SCZ) and autism spectrum disorders (ASD) is grappling with their remarkable genetic and phenotypic heterogeneity. As such, taking a `genetics first' approach—i.e., ascertainment and comprehensive phenotyping of individuals with specific, known genetic variants—offers an alternative, biologically-tractable framework to dissecting genetic mechanisms underlying intermediate phenotypes of brain development, cognition, and behavior. Copy number variants (deleted or duplicated DNA segments ≥ 50 basepairs; CNVs) at the 22q11.2 locus are especially compelling models because they confer some of the largest known genetic risk for psychiatric disorders and include highly conserved genes critical for brain and cognitive development. The 22q11.2 deletion results from a 1.5–3 Mb hemizygous deletion on the long arm of chromosome 22 and has an estimated prevalence of 1 in 3,000–4,000 live births. In addition to medical comorbidities, the deletion is one of the greatest known genetic risks for SCZ, with a 25-fold risk increase compared to the general population. It is also associated with greater risk for other developmental neuropsychiatric disorders such as ASD. Yet, very little is known about the reciprocal 22q11.2 duplication phenotype, in part due to its more recent discovery as a recurrent CNV. While the phenotype is highly variable, it appears to confer high risk for ASD and specific language impairment. Intriguingly, multiple population-based studies have now shown the duplication to be significantly less common in SCZ cases than in the general population, suggesting the first putative protective mutation for SCZ. This notable distinction between risk and protective factors for SCZ suggests that gene-dosage specificity may underlie disease evolution. This project will leverage a large cohort of extensively phenotyped individuals with 22q11.2 deletions (n=91) or duplications (n=34), as well as demographically comparable controls (n=82). This will be the first study to investigate reciprocal effects of 22q11.2 CNVs on gene expression, brain, and behavior. Specifically, our aims are to: (i) establish the effect of 22q11.2 CNVs on multiple cognitive and behavioral measures relevant to SCZ and/or ASD (Aim 1), (ii) investigate transcriptome-wide dysregulation of gene expression by identifying networks of co-expressed genes resulting from a 22q11.2 deletion versus duplication and use enrichment analysis to infer dysregulated biological pathways (Aim 2), and (iii) probe biological pathways predictive of brain and behavioral phenotypes in these reciprocal CNVs (Aim 3). This integrative, multimodal approach aims to elucidate biological pathways and brain biomarkers which may differentiate risk versus protective factors for psychosis or converging factors for ASD risk, in the context of this highly-penetrant CNV, with the primary goal of providing novel insights into how these CNVs disrupt the brain and contribute to disease pathogenesis.

项目摘要/摘要 在揭示发育性神经精神疾病的生物学机制方面的主要挑战 精神分裂症(SCZ)和自闭症谱系障碍(ASD)正在努力解决它们显著的遗传和 表型异质性。因此，采取“遗传学优先”的方法--即，查明和全面 对具有特定已知基因变异的个体进行表型分型--提供了一种生物学上易于处理的替代方案 剖析大脑发育中间表型潜在遗传机制的框架， 认知和行为。拷贝数变异(删除或复制的DNA片段≥50碱基；CNV)在 22q11.2基因座是特别引人注目的模型，因为它们赋予了一些已知的最大的遗传 精神障碍的风险，包括对大脑和认知发育至关重要的高度保守的基因。 22q11.2的缺失是由于22号染色体长臂上1.5-3Mb的半合子缺失所致 据估计，每3,000-4,000名活产儿中就有1名。除了医学上的合并症，删除的是 已知的SCZ最大的遗传风险之一，与一般情况下相比，风险增加了25倍 人口。它还与其他发育性神经精神障碍的风险更大有关，如 ASD.然而，人们对相互作用的22q11.2重复表型知之甚少，部分原因是它最近 发现为复发性CNV。虽然表型有很高的变异性，但它似乎具有患ASD的高风险。 和特定的语言障碍。有趣的是，多项基于人群的研究现在表明 与普通人群相比，SCZ患者中的复制现象明显较少，这表明第一 推测为SCZ的保护性突变。SCZ的危险因素和保护因素之间的显著区别 提示基因剂量特异性可能是疾病进化的基础。这个项目将利用一个大的队列 具有22q11.2缺失(n=91)或重复(n=34)的广泛表型个体，以及 人口学上可比的对照(n=82)。这将是第一个研究相互影响的研究。 22q11.2 CNV对基因表达、脑和行为的影响。具体来说，我们的目标是：(I)确立 22q11.2与SCZ和/或ASD相关的多种认知和行为测量的CNV(目标1)，(2) 通过鉴定共表达的网络来研究转录组范围的基因表达失调 由22q11.2缺失和复制产生的基因，并使用富集化分析来推断失调 生物学途径(目标2)，和(Iii)探索预测大脑和行为表型的生物学途径 在这些相互的CNV中(目标3)。这种综合的、多模式的方法旨在阐明生物途径 和脑生物标记物，可以区分精神病的危险因素和保护因素或趋同因素 对于ASD风险，在这种高度渗透的CNV的背景下，主要目标是提供对 这些CNV是如何扰乱大脑并促进疾病发病机制的。