Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

威廉姆斯综合征基因-大脑关系的多模态神经影像

• 批准号: 10703927
• 负责人: Karen FAITH Berman
• 金额: $ 190.14万
• 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/10703927
• 关键词: 7q11.23; Address; Affect; Age; Amygdaloid structure; Anterior; Aortic Valve Stenosis; Area; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; Cerebellum; Characteristics; Child; Childhood; Chromosome 7; Clinical; Cognition; Communities; Complement; Complex; Copy Number Polymorphism; DNA; Data; Data Collection; Development; Diffusion Magnetic Resonance Imaging; Disease; Dose; 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; 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; Persons; 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; Software Tools; Stimulus; Structure; Surface; Syndrome; System; Techniques; Testing; Variant; Veins; Visual; Visuospatial; Williams Syndrome; Work; analysis pipeline; 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; in vivo; indexing; intraparietal sulcus; longitudinal analysis; microdeletion; morphometry; multimodal neuroimaging; myelination; neural; neural circuit; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatric disorder; novel; response; sex; skills; social; social cognition; social influence; 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, 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, with additional in vivo neuroimaging measurements of myelination, 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 (for WS) or duplicated (Dup7) strand of the chromosomal 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. We have also formalized our longitudinal analysis methods and have made available to the neuroimaging community a software tool to address some of the challenges of analyzing longitudinal neuroimaging data (Chen et al., 2021). In addition, we have established processing pipelines for analyzing the diverse array of neuroimaging data types being collected. 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继续致力于通过一系列正在进行的多模态神经影像学研究，发现新的遗传对大脑结构，功能和临床相关行为和认知的贡献，这些研究针对7q11.23威廉姆斯综合征（WS）基因组区域拷贝数变异（该基因座的半合子微缺失或连续DNA片段重复）的个体。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。通过多种神经影像学技术，包括体素和表面为基础的皮质形态测量，扩散张量成像，功能磁共振成像，我们已经建立了WS的视觉空间结构缺陷与会聚顶内沟改变。具体来说，在这个大脑区域，我们已经表明，个人与WS港口破坏神经的完整性，改变激活过程中的空间判断，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，在追求系统水平的相关性的过度社交和非社交焦虑观察WS，我们发现减少杏仁核激活诱发观看图片的脸与恐惧诱导的内容，相反，增加杏仁核反应的非社会可怕的图片，异常与改变前额叶调节结构方程模型。我们还发现了前额叶结构、功能和区域间连接的会聚性改变，这些改变可以预测WS人格的特征。今年的努力集中在视觉空间和社会情感系统完整性的这些相同结构和功能测量的数据收集上，以及髓鞘形成的额外体内神经成像测量，在越来越多的有和没有WS关键区域拷贝数变异的儿童队列中（即，受影响基因拷贝数为1个WS、2个典型发展TD或3个Dup7的个体）作为我们纵向WS神经发育计划的一部分。 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增加，总体大脑大小（Dup7>TD>WS）增加，但相对小脑大小（WS>TD>Dup7）减少。有趣的是，这两种Dup7表型（大脑体积较大，小脑相对较小）在自闭症文献中均有描述，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，我们正在进行类似的基因剂量分析，对整个大脑的更多局部形态测量，以及局部脑回化指数和静息状态全脑连接进行分析，后者使用连接组关联研究方法以及独立成分和双回归分析。 为了了解威廉姆斯综合征基因组区域拷贝数变异个体间的异质性，我们已经开始研究染色体区域剩余（WS）或重复（Dup 7）链中单核苷酸多态性和遗传单倍型的影响。我们已经开发了新的方法来实现专门的基因分型SNP芯片数据，并应用这些方法在概念验证工作中测试的假设，ELN基因（而不是其他7q11.23基因）的常见变异将预测有临床意义的异常主动脉结构。我们能够在受影响的区域产生单倍体和三倍体基因型调用，并确定了与WS参与者的主动脉瓣狭窄相关的单核苷酸多态性和Dup7参与者的主动脉扩张保护。正在进行的工作将集中于了解WS区域内的序列变异如何倾向于神经表型的变异性，例如我们观察到的以基因剂量依赖性方式与7q11.23拷贝数变异相关的上述宏观结构特征。 我们的WS发展队列的初步数据已经证明顶叶功能减退，在视觉空间的挑战，沿着改变社会网络激活过程中的社会显着的刺激，一致的假设，即视觉空间和社会神经生物学差异WS植根于早期生活。最近，在这个队列中，我们发现了非典型模式的顶内沟功能连接WS，其功能与视觉网络的合作性减弱，但相比之下，增强社会的大脑网络的联系。这项工作提供了一个基于神经回路的观点，这些不同的视觉空间和社会电路如何整合在7q11拷贝变异的背景下，并在该人群的行为特征的背景下。 我们还将我们的纵向分析方法正式化，并向神经影像学界提供了一种软件工具，以解决分析纵向神经影像学数据的一些挑战（Chen等人，2021年）。此外，我们还建立了处理管道，用于分析收集的各种神经成像数据类型。 总体而言，该项目旨在不仅扩大知识的WS相关的大脑系统在儿童时期，但也确定发展轨迹（整个童年）和基因剂量反应特征的神经异常的视觉空间和社会情绪的变化，在这种综合征使用纵向，重复测量设计。这方面的初步概念验证分析已经取得成功。虽然数据积累需要多年的仔细和协调一致的努力才能完成，但这些研究在揭示基因对大脑发育的贡献方面的潜力是巨大的。 本工作包括以下研究：NCT 01132885、NCT 00004571、NCT 00001258