Understanding Rare Genetic Variation and Disease Risk: A Global Neurogenetics Initiative

项目摘要 拷贝数变异(CNV)与神经发育率的极大提高有关 精神障碍(NPD)。到目前为止，努力的重点是少数最频繁的复发 CNV。因此，CNV相关变异之间关系的指导原则 这些CNV中包含的大脑结构和基因的功能尚不清楚。此外， CNV相关脑变异所介导的行为特征及其与 人们对特发性NPD知之甚少。为了解决这些问题，我们建议利用现有的 队列，以组装到目前为止最大的神经成像基因组数据集(n~140,000)。决赛 聚合数据集将包括约29,000名CNV≥50kb携带者，包括编码基因。CNV 将在所有数据集上使用相同的管道进行标识。多模式神经成像数据，包括 T1加权结构图像、T1w/T2w比值图像、静息状态功能磁共振成像和弥散成像， 将使用相同的协调管道进行处理。我们的团队，拥有医疗和医疗方面的专业知识 统计遗传学、数学建模和脑成像将在4个站点协同工作 在美国、加拿大和挪威，以实现以下具体目标： 目标1：描述最常见和公认的复发性NPD的影响 相关CNV对脑结构和功能的影响。我们还将调查常见的变种 (多基因评分)调节NPD-CNV对神经成像衍生测量的影响。 目的2：研究全球CNV负荷对脑结构和功能的影响。 风险分值。一种将基因功能注释与CNV相关神经成像联系起来的方法 改装。绝大多数临床相关的CNV都太罕见，不能单独研究。vbl.使用 基于基因注释的CNV风险评分，我们将研究(总体)对大脑的影响 所有含有编码基因的稀有CNV(n~29,000)的结构。 目标3：将CNV相关神经成像特征与RDoC域和精神病学联系起来 表型。我们将测试上面确定的CNV神经成像特征与 认知和精神病理学的维度测量，大，深表型，未选择 人口队列。 这项全球CNV神经成像倡议将增强识别机制的能力 调节缺失和复制对大脑结构的影响。这一协调一致的努力将 促进我们对基因变异增加NPD易感性的机制的理解 比如自闭症和精神分裂症。

Project Abstract Copy number variants (CNVs) are associated with greatly elevated rates of neurodevelopmental psychiatric disorders (NPDs). Efforts to date have focused on a handful of the most frequent recurrent CNVs. As a result, the guiding principles underlying relationships between CNV-related variations in brain architecture and the function of genes encompassed in these CNVs are unknown. In addition, the behavioral features mediated by CNV-related brain variations, and their convergence with findings in idiopathic NPDs, are poorly understood. To address these questions, we propose to utilize existing cohorts to assemble the largest neuroimaging genomic dataset to date (n~140,000). The final aggregated dataset will include ~29,000 carriers of CNVs ≥ 50kb, encompassing coding genes. CNVs will be identified using the same pipeline across all datasets. Multimodal neuroimaging data, including T1-weighted structural images, T1w/T2w ratio images, resting-state functional MRI, and diffusion MRI, will be processed using the same harmonized pipelines. Our team, with expertise in medical and statistical genetics, mathematical modeling, and brain imaging, will work collaboratively across 4 sites in the USA, Canada, and Norway to address the following Specific Aims: Aim 1: Characterize the effect of the most frequent and well-established recurrent NPD- associated CNVs on brain structure and function. We will also investigate if common variants (polygenic scores) modulate the effects of NPD-CNVs on neuroimaging-derived measures. Aim 2: Investigate effects on brain structure and function of global CNV burden using CNV- risk scores. A method to link functional annotations of genes to CNV-associated neuroimaging alterations. The vast majority of clinically relevant CNVs are too rare to be studied individually. Using CNV-risk scores based on gene annotations, we will investigate (in aggregate) the effects on brain architecture of all rare CNVs (n~29,000) containing coding genes. Aim 3: Linking CNV-associated neuroimaging signatures to RDoC domains and psychiatric phenotypes. We will test the relationship between CNV-neuroimaging signatures identified above and dimensional measures of cognition and psychopathology in large, deeply phenotyped, unselected population cohorts. This worldwide CNV neuroimaging initiative will boost power to identify mechanisms that mediate the effects of deletions and duplications on brain architecture. This concerted endeavor will advance our understanding of mechanisms by which genetic variants increase vulnerability for NPDs such as autism and schizophrenia.