Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

威廉姆斯综合征基因-大脑关系的多模式神经影像

• 批准号: 10266603
• 负责人: Karen FAITH Berman
• 金额: $ 145.43万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266603
• 关键词: 7q11.23; Affect; Age; Amygdaloid structure; Anterior; Aortic Valve Stenosis; Area; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; Cerebellum; Characteristics; Child; Childhood; Chromosome 7; Clinical; Cognition; Complement; Complex; Copy Number Polymorphism; DNA; Data; Data Collection; Development; Diffusion Magnetic Resonance Imaging; Disease; Dose; Emotional; Equation; Face; Fiber; Fright; Functional Magnetic Resonance Imaging; Gene Dosage; General Population; Genes; Genetic; Genetic Determinism; Genomic Segment; Genotype; Handedness; Haploidy; Haplotypes; Heterogeneity; Impairment; Incidence; Individual; Insula of Reil; Intellectual functioning disability; Judgment; Knowledge; Life; Light; Link; Literature; Live Birth; Magnetic Resonance Imaging; Measurement; Measures; Methodology; Methods; Mind; Modeling; Molecular Abnormality; Multimodal Imaging; Mutation; Nature; Neurobiology; Neurodevelopmental Disorder; Parietal; Participant; Pathology; Pattern; Personality; Phenotype; Plant Roots; Population Characteristics; Positron-Emission Tomography; Rare Diseases; Regression Analysis; Regulation; Rest; SNP array; SNP genotyping; Seminal; Series; Single Nucleotide Polymorphism; Social Behavior; Social Network; Stimulus; Structure; Surface; Syndrome; System; Techniques; Testing; Variant; Veins; Visual; Visuospatial; Williams Syndrome; Work; autism spectrum disorder; base; behavioral phenotyping; boys; brain size; clinical predictors; clinically relevant; cognitive function; cohort; connectome; contrast enhanced; design; experience; experimental study; gray matter; human model; indexing; intraparietal sulcus; microdeletion; morphometry; multimodality; neural circuit; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatric disorder; novel; relating to nervous system; response; sex; skills; social; social cognition; success; translational neuroscience

The Clinical and Translational Neuroscience Branch continues to work toward discovery of novel genetic contributions to brain structure, function, and clinically relevant behavior and cognition through a series of ongoing multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region (hemizygous microdeletion or duplication of a contiguous segment of DNA at this locus). These studies have been responsible for seminal advances in elaborating the neural underpinnings of both visuospatial and socio-emotional aspects of the 7q11.23 phenotype. Via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging, and functional MRI, we have established that the visuospatial construction deficits in WS are linked to convergent intraparietal sulcus alterations. Specifically, in this brain region, we have shown that individuals with WS harbor disrupted neural integrity, altered activation during spatial judgments, gray matter volume and sulcal depth reductions, and associated neural fiber tract anomalies. Similarly, in pursuit of systems-level correlates of the hypersociability and non-social anxiety observed in WS, we have found decreased amygdala activation evoked by viewing pictures of faces with fear-inducing content and, conversely, increased amygdala response to non-social frightening pictures, abnormalities that were linked to altered prefrontal regulation in structural equation models. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity that predict the characteristic WS personality. Efforts this year have focused on data collection of these same structural and functional measurements of visuospatial and socio-emotional systems integrity in a growing cohort of children with and without WS critical region copy number variation (i.e., individuals with one in WS, two in typically developing TD, or three in Dup7 copies of affected genes) as part of our longitudinal WS neurodevelopmental initiative. In proof-of-concept work aimed at establishing neurostructural gene-dosage effects, we have found increasing overall brain size (Dup7>TD>WS) but decreasing relative cerebellar size (WS>TD>Dup7) with copy number of affected genes. Interestingly, both of these Dup7 phenotypes (larger brain size and relatively smaller cerebellum) have been described in the autism literature, particularly in boys, although these findings are not without controversy. Following this work, we are undertaking similar gene-dosage analyses of more localized morphometry throughout the brain, as well as local gyrification index and resting-state whole-brain connectivity, the latter using a connectome-wide association study approach as well as independent component and dual-regression analyses. In pursuit of understanding the heterogeneity across individuals with copy number variation in the Williams Syndrome genomic region, we have embarked on studies of the effects of single nucleotide polymorphisms and genetic haplotypes in the remaining or duplicated strand of the region. We have developed novel methods to achieve specialized genotyping from SNP-chip data and applied these methods in proof-of-concept work testing the hypothesis that common variation in the ELN gene and not other 7q11.23 genes would predict clinically meaningful abnormalities of aortic structure. We were able to generate haploid and triploid genotype calls across the affected region and identified a single nucleotide polymorphism associated with aortic stenosis in WS participants and protection from aortic dilation in Dup7 participants. Ongoing work will focus on understanding how sequence variation within the WS region predisposes to variability in neural phenotypes, such as above-mentioned macrostructural characteristics that we have observed to be associated with 7q11.23 copy number variation in a gene-dose dependent manner. Preliminary data from our WS developmental cohort has already demonstrated parietal hypofunction during visuospatial challenge along with altered social network activation during processing of socially salient stimuli, consistent with the hypothesis that both visuospatial and social neurobiological differences in WS are rooted in early life. Recently in this cohort, we have uncovered atypical patterns of intraparietal sulcus functional connectivity in WS, which feature diminished cooperativity with visual networks but, in contrast, enhanced social brain network linkage. This work offers a neural circuit-based view of how these diverse visuospatial and social circuits integrate in the context of 7q11 copy variation and in the context of the behavioral characteristics of this population (Gregory et al., 2019). Overall, this project seeks not only to expand knowledge of the WS-related brain systems in childhood, but also to identify developmental trajectory (throughout childhood) and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome using a longitudinal, repeated measures design. Preliminary proof-of-concept analyses in this vein have already been successful. Though data accrual will require years of careful and concerted effort to complete, the potential for these studies to shed unprecedented light on genetic contributions to brain development is enormous. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258

临床和转化神经科学分支通过对 7q11.23 威廉姆斯综合征 (WS) 拷贝数变异个体进行一系列正在进行的多模式神经影像学研究，继续致力于发现对大脑结构、功能以及临床相关行为和认知的新遗传贡献。 ) 基因组区域（该位点的连续 DNA 片段的半合子微缺失或重复）。这些研究在阐述 7q11.23 表型的视觉空间和社会情感方面的神经基础方面取得了开创性的进展。通过多种神经影像技术，包括基于体素和表面的皮质形态测量、扩散张量成像和功能性 MRI，我们已经确定 WS 的视觉空间结构缺陷与会聚的顶内沟改变有关。具体来说，在这个大脑区域，我们发现患有 WS 的个体存在神经完整性破坏、空间判断过程中的激活改变、灰质体积和脑沟深度减少以及相关的神经纤维束异常。 同样，为了追寻在 WS 中观察到的超社交性和非社交焦虑的系统级关联，我们发现，观看带有恐惧诱导内容的面孔图片时，杏仁核激活会减少，相反，杏仁核对非社交恐惧的反应会增加图片，与结构方程模型中前额叶调节改变有关的异常。我们还发现了前岛叶结构、功能和区域间连接的趋同性改变，这些改变可以预测 WS 的特征特征。今年的工作重点是在越来越多的具有或不具有 WS 关键区域拷贝数变异的儿童群体中，收集这些相同的视觉空间和社会情感系统完整性的结构和功能测量数据（即，具有 WS 关键区域拷贝数变异的个体，通常具有 WS 拷贝数变异的个体）作为我们纵向 WS 神经发育计划的一部分，开发 TD（或受影响基因的 Dup7 拷贝中的三个）。 在旨在建立神经结构基因剂量效应的概念验证工作中，我们发现随着受影响基因的拷贝数，整体大脑尺寸增加（Dup7>TD>WS），但相对小脑尺寸减小（WS>TD>Dup7）。有趣的是，这两种 Dup7 表型（较大的大脑尺寸和相对较小的小脑）在自闭症文献中都有描述，特别是在男孩中，尽管这些发现并非没有争议。在这项工作之后，我们正在对整个大脑的更局部形态测量以及局部回旋指数和静息态全脑连接性进行类似的基因剂量分析，后者使用全连接组关联研究方法以及独立成分和对偶回归分析。 为了了解威廉姆斯综合症基因组区域中具有拷贝数变异的个体之间的异质性，我们开始研究单核苷酸多态性和遗传单倍型对该区域的剩余或重复链的影响。我们开发了新方法来从 SNP 芯片数据中实现专门的基因分型，并将这些方法应用于概念验证工作，测试以下假设：ELN 基因而非其他 7q11.23 基因的常见变异可以预测有临床意义的主动脉结构异常。我们能够在受影响区域生成单倍体和三倍体基因型识别，并鉴定出与 WS 参与者的主动脉瓣狭窄相关的单核苷酸多态性以及与 Dup7 参与者的主动脉扩张保护相关的单核苷酸多态性。正在进行的工作将侧重于了解 WS 区域内的序列变异如何导致神经表型的变异，例如我们观察到的上述宏观结构特征与 7q11.23 拷贝数变异以基因剂量依赖性方式相关。 我们的 WS 发育队列的初步数据已经证明，在视觉空间挑战期间，顶叶功能减退，以及在处理社会显着刺激期间社交网络激活的改变，这与 WS 的视觉空间和社会神经生物学差异植根于早期生活的假设一致。最近，在这个队列中，我们发现了 WS 中顶内沟功能连接的非典型模式，其特征是与视觉网络的协作性减弱，但相反，社交脑网络的联系增强。 这项工作提供了基于神经回路的视图，了解这些不同的视觉空间和社会回路如何在 7q11 拷贝变异的背景下以及该人群的行为特征背景下整合（Gregory 等人，2019）。 总体而言，该项目不仅旨在扩大对儿童期 WS 相关大脑系统的了解，而且还利用纵向、重复测量设计。这方面的初步概念验证分析已经取得了成功。尽管数据积累需要多年的仔细和共同努力才能完成，但这些研究在揭示遗传对大脑发育的贡献方面具有前所未有的潜力是巨大的。 这项工作包括以下研究：NCT01132885、NCT00004571、NCT00001258