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: 9920597
• 负责人: Amy Lin
• 金额: $ 3.52万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920597
• 关键词: 22q; 22q11.2; Affect; Area; Behavior; Behavioral; Biological; Biological Markers; Brain; Clinical; Cognition; Cognitive; 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; behavioral phenotyping; brain behavior; brain dysfunction; cognitive ability; cognitive development; cohort; comorbidity; 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.

项目概要/摘要 揭示发育性神经精神疾病（如 精神分裂症 (SCZ) 和自闭症谱系障碍 (ASD) 正在努力解决其显着的遗传和 表型异质性。因此，采取“遗传学优先”的方法，即确定和综合 对具有特定已知遗传变异的个体进行表型分析——提供了一种生物学上可处理的替代方法 剖析大脑发育中间表型背后的遗传机制的框架， 认知、行为。拷贝数变异（删除或重复的 DNA 片段≥ 50 个碱基对；CNV） 22q11.2 基因座是特别引人注目的模型，因为它们赋予了一些最大的已知遗传基因 精神疾病的风险，包括对大脑和认知发育至关重要的高度保守的基因。 22q11.2 缺失是由 22 号染色体长臂上 1.5-3 Mb 的半合子缺失导致的 据估计，每 3,000-4,000 名活产儿中就有 1 人患病。除了医疗合并症之外，删除还包括 SCZ 已知的最大遗传风险之一，与一般情况相比风险增加 25 倍 人口。它还与其他发育性神经精神疾病的更大风险相关，例如 自闭症谱系障碍。然而，人们对倒数 22q11.2 重复表型知之甚少，部分原因是其较新的 发现为复发性 CNV。虽然表型变化很大，但它似乎会带来 ASD 的高风险 以及特定的语言障碍。有趣的是，多项基于人群的研究现已表明 与一般人群相比，SCZ 病例中的重复现象明显较少，这表明第一个 SCZ 的假定保护性突变。 SCZ 的风险因素和保护因素之间的显着区别 表明基因剂量特异性可能是疾病进化的基础。该项目将利用大量人群 具有 22q11.2 缺失 (n=91) 或重复 (n=34) 的广泛表型个体，以及 人口统计学上可比较的对照（n=82）。这将是第一项调查相互影响的研究 22q11.2 CNV 对基因表达、大脑和行为的影响。具体来说，我们的目标是：（i）确定 22q11.2 与 SCZ 和/或 ASD 相关的多种认知和行为测量的 CNV（目标 1）、(ii) 通过识别共表达网络来研究基因表达的转录组范围失调 22q11.2 缺失与重复产生的基因，并使用富集分析来推断失调 生物途径（目标 2），以及 (iii) 探索预测大脑和行为表型的生物途径 在这些相互的 CNV 中（目标 3）。这种综合的多模式方法旨在阐明生物学途径 和大脑生物标志物，可以区分精神病的风险与保护因素或聚合因素 针对 ASD 风险，在这种高度渗透的 CNV 背景下，主要目标是提供新颖的见解 这些 CNV 如何破坏大脑并导致疾病发病机制。