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

摘要 精神病神经影像学的未满足需求是基准的标准发展参考框架 神经发育状况的研究，如精神分裂症的精神病谱（PS）。使用 建模方法已被证明是成功的非成像生长图表在临床儿科，并在我们的 初步工作集中在一组有限的全球脑MRI特征，我们建议利用数据 从我们的多站点脑图联盟，以产生大脑成熟的计算图表， 一组跨解剖尺度的大脑形态学特征。我们的联盟旨在成为最大和最 包括可能的，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 超过300台MR扫描仪。使用先进的、完全可再现的流水线进行质量控制、图像 处理和协调，多尺度脑图将确定规范性趋势和增长的里程碑 其可用于对新的个体脑部扫描或一组扫描进行基准测试，同时控制研究- 具体的技术难题。我们将创建并维护一个开放资源，以传播这些图表供使用 其他研究人员。我们将使用脑图表来识别发育成像表型的集群-脑 以成长图表规范为基准的概况-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可遗传的大脑轮廓，我们假设这将显示 基因型-年龄效应沿着皮层成熟的感觉-联想（SA）轴沿着组织， 假设出现PS风险的发育时期（目标1）。我们将进行基因组研究， 全转录组关联研究，以确定受功能活性影响的大脑概况 与PS风险相关的遗传变异（目标2）。我们将对具有以下特征的个体进行大脑轮廓分型： 在我们的联合病例对照研究（超过2000次MRI）中进行PS诊断，以表征PS亚型，其中 在经历长期成熟的联合皮层中，沿着SA轴的偏离最为显著，沿着SA轴的偏离最显著 度过青春期因此，在一项新的研究中，任何个人的图表基准大脑轮廓都可以 特征在于量化与该PS亚型的相似性的负荷评分，并且我们将评估 PS亚型负荷评分与多个纵向研究中PS症状演变的相关性 在宾夕法尼亚大学进行的PS随访研究（超过2200个纵向MRI，800个 参与者，450名PS，年龄8-35岁），将为该提案（目标3）进行汇总和协调。这 提案的首要目标是创建一个实用的脑图资源，并展示其 PS大脑发育研究的变革潜力。这项工作利用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。 累积起来，拟议的研究将为我们对典型大脑的理解提供实质性的进展。 发育和改变PS的神经发育。

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.