Precision brain charts for imaging-genomics of schizophrenia and the psychosis spectrum

摘要 未得到满足的精神神经成像需求是基准的标准发展参照系 对神经发育状况的研究，如精神分裂症和精神病谱系(PS)。使用 建模方法已被证明成功地用于临床儿科和我们的 初步工作集中在有限的一组全局脑MRI特征上，我们建议利用数据 来自我们的多站点脑图联盟，为更富有的人制作大脑成熟的计算图表 一组跨越解剖尺度的脑形态特征。我们的目标是成为最大和最 可能包括，初步数据涵盖整个生命周期，超过130,000次MRI扫描，超过100,000次 个人和300多台磁共振扫描仪。使用先进的、完全可复制的管道进行质量控制、图像 处理和协调，多尺度脑图将定义规范的发展趋势和里程碑 它可以用来对新的单个大脑扫描或一组扫描进行基准测试，同时控制研究- 具体的技术问题。我们将创建并维护一个开放资源来传播这些图表以供使用 由其他研究人员提供。我们将使用脑图来识别发育成像表型的簇-大脑 以增长图表标准为基准的概况-具有类似形状的成熟轨迹。纵向 对双胞胎数据集的分析将特别描绘出可遗传的大脑图谱，我们假设这将显示 沿着皮质成熟的感觉-联想(SA)轴组织的按年龄的基因型效应， 假设出现多发性硬化症风险的发展阶段(目标1)。我们将进行基因组测试--以及 全转录组关联研究以确定受功能活跃影响的大脑特征 与PS风险相关的遗传变异(目标2)。我们将对患有脑部疾病的患者进行脑部轮廓亚型分析 我们联合病例对照研究中的PS诊断(超过2000个磁共振成像)，以确定PS亚型的特征，其中 在经历了较长时间成熟的联合皮质中，沿SA轴的偏差最明显 一直到青春期。因此，在一项新的研究中，任何一个人以图表为基准的大脑概况都可以 以量化与此PS子类型的相似性的加载分数为特征，我们将评估 PS亚型负荷评分与PS症状演变的关系 在宾夕法尼亚大学进行的PS后续研究(超过2200项纵向磁共振成像，800项 参与者，450人，8-35岁)，将为这项建议(目标3)汇集和协调。这 提案的首要目标是创建一个实用的脑图资源，并展示其 多发性硬化症脑发育研究的变革潜力。这项工作充分利用了PI和组装 团队在精神病学和发育脑成像、成像遗传学和神经信息学方面的专业知识。 总而言之，拟议中的研究将为我们对典型大脑的理解提供实质性的进步 PS的发育和神经发育的改变。

ABSTRACT An unmet need for psychiatric neuroimaging is a standard developmental frame of reference to benchmark studies of neurodevelopmental conditions such as schizophrenia the psychosis spectrum (PS). Using a modelling approach that has proven successful for non-imaging growth charts in clinical pediatrics, and in our preliminary work that was focused on a limited set of global brain MRI features, we propose to leverage data from our multi-site Brain Chart Consortium to produce computational charts of brain maturation for a far richer set of brain morphological features across anatomical scales. Our Consortium aims to be the largest and most inclusive possible, with preliminary data covering the entire lifespan, over 130,000 MRI scans, over 100,000 individuals and over 300 MR scanners. Using advanced, fully-reproducible pipelines for quality control, image processing and harmonization, multi-scale brain charts will define normative trends and milestones of growth which can be used to benchmark a new individual brain scan, or group of scans, while controlling for study- specific technical confounds. We will create and maintain an open resource to disseminate these charts for use by other researchers. We will use brain charts to identify clusters of developmental imaging phenotypes – brain profiles benchmarked by growth chart norms – with similarly-shaped maturational trajectories. Longitudinal analysis of twin datasets will specifically delineate heritable brain profiles, which we hypothesize will show genotype-by-age effects organized along the sensory-to-association (SA) axis of cortical maturation, in developmental epochs where risk for PS is hypothesized to emerge (Aim 1). We will perform genome- and transcriptome-wide association studies to identify brain profiles that are influenced by functionally active genetic variants associated with risk for PS (Aim 2). We will perform brain profile subtyping of individuals with PS diagnoses in our Consortium case-control studies (over 2000 MRIs), to characterize a PS subtype where deviations are most prominent along the SA axis in association cortices that undergo prolonged maturation through adolescence. Any individual’s chart-benchmarked brain profile, in a new study, can thus be characterized with a loading score that quantifies similarity to this PS subtype, and we will evaluate the association of the PS subtype loading score with the evolution of PS symptoms across multiple longitudinal follow-up studies of PS conducted at the University of Pennsylvania (over 2200 longitudinal MRIs, 800 participants, 450 with PS, age 8-35) that will be pooled and harmonized for this proposal (Aim 3). This proposal’s overarching goal is to create a practically useful brain chart resource and to demonstrate its transformative potential for studies of brain development in PS. This work capitalizes on the PI and assembled team’s expertise in psychiatric and developmental brain imaging, imaging-genetics and neuroinformatics. Cumulatively, the proposed research will provide a substantial advance in our understanding of typical brain development and altered neurodevelopment in PS.