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

项目总结/摘要 揭示发育性神经精神疾病的生物学机制的主要挑战， 精神分裂症（SCZ）和自闭症谱系障碍（ASD）正在努力解决其显着的遗传和 表型异质性因此，采取“遗传学第一”的方法，确定和综合 对具有特定的、已知的遗传变异的个体进行表型分析， 框架来解剖大脑发育中间表型的遗传机制， 认知和行为。拷贝数变异（≥ 50个碱基对的DNA片段缺失或重复; 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已知的最大的遗传 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的半合子缺失引起的， 估计流行率为每3 000 - 4 000名活产婴儿中有1人。除了医学合并症，删除是 已知SCZ最大的遗传风险之一，与一般风险相比， 人口它还与其他发育性神经精神障碍的风险更大有关， 自闭症然而，关于22q11.2的相互重复表型知之甚少，部分原因是它是最近才发现的。 发现为复发性CNV。虽然表型是高度可变的，它似乎赋予高风险的ASD 和特殊的语言障碍有趣的是，多项基于人群的研究表明， 重复在SCZ病例中比在一般人群中明显不常见，这表明第一个 SCZ的推定保护性突变。SCZ的风险因素和保护因素之间的显著区别 表明基因剂量特异性可能是疾病演变的基础。这个项目将利用一个庞大的群体， 22q11.2缺失（n=91）或重复（n=34）的广泛表型个体，以及 人口统计学可比对照组（n=82）。这将是第一项研究，以调查相互影响的 22q11.2 CNVs对基因表达、大脑和行为的影响具体而言，我们的目标是：（一）建立的影响， 22q11.2与SCZ和/或ASD相关的多项认知和行为测量的CNV（目的1），（ii） 通过鉴定共表达的网络研究基因表达的转录组范围的失调 22q11.2缺失与重复导致的基因，并使用富集分析来推断失调 生物学途径（目标2），以及（iii）探测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 对于ASD风险，在这种高度渗透的CNV背景下，主要目标是提供新的见解， 这些CNV如何破坏大脑并促进疾病发病机制。

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.