Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

临床和翻译神经科学分部继续致力于通过对7q11.23威廉姆斯综合征(WS)基因组区域拷贝数变化(该基因座上连续DNA片段的半合子微缺失或复制)个体进行的一系列持续的多模式神经成像研究，发现对大脑结构、功能以及临床相关行为和认知的新的遗传贡献。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。通过多种神经成像技术，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磁共振成像，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。具体地说，在这个大脑区域，我们已经证明了WS患者的神经完整性受到破坏，在空间判断过程中激活改变，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，在追求WS中观察到的高度社交和非社交焦虑的系统水平相关性的过程中，我们发现通过观看带有恐惧内容的面孔的图片而引起的杏仁核激活减少，相反，杏仁核对非社交恐惧图片的反应增加，这些异常与结构方程模型中改变的前额叶调节有关。我们还发现了前岛结构、功能和区域间连通性的汇聚性变化，这些变化预测了WS的特征个性。作为我们纵向WS神经发育计划的一部分，今年的工作重点是收集越来越多患有和不患有WS关键区域拷贝数变异的儿童(即WS中有1个在WS中，2个在典型发育中的TD中，或在Dup7中有3个受影响基因拷贝)的视觉空间和社会情绪系统完整性的结构和功能测量的数据。 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，总体大脑大小(Dup7&gt；TD&gt；WS)增加，但相对小脑大小(WS&gt；TD&gt；Dup7)减小。有趣的是，这两种Dup7表型(较大的大脑和相对较小的小脑)都在自闭症文献中被描述过，特别是在男孩中，尽管这些发现并不是没有争议。在这项工作之后，我们正在进行类似的基因剂量分析，对整个大脑进行更局部化的形态测量，以及局部回旋指数和静息状态的全脑连通性，后者使用连接组广泛的关联研究方法以及独立成分和双回归分析。 为了了解Williams综合征基因组区域拷贝数变异的个体之间的异质性，我们开始研究该区域剩余或重复链上的单核苷酸多态和遗传单倍型的影响。我们已经开发了新的方法来从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，验证了ELN基因而不是其他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的假设。我们能够在受影响的区域产生单倍体和三倍体的基因型呼叫，并在WS参与者中发现与主动脉狭窄相关的单核苷酸多态，在Dup7参与者中发现与主动脉扩张保护相关的单核苷酸多态性。正在进行的工作将集中在了解WS区域内的序列变异如何易于神经表型的变异，例如我们观察到的上述宏观结构特征以基因剂量依赖的方式与7q11.23拷贝数变异相关。 我们的WS发育队列的初步数据已经表明，在视觉空间挑战中，顶叶功能低下，以及在处理社交显著刺激过程中社会网络激活的改变，这与WS的视觉空间和社交神经生物学差异都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的顶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，社交大脑网络连接增强。这项工作提供了一种基于神经回路的观点，即这些不同的视觉空间和社交回路如何在7q11拷贝变异的背景下以及在这一人群的行为特征的背景下整合(Gregory等人，2019年)。 总体而言，该项目不仅寻求扩大儿童WS相关脑系统的知识，而且使用纵向、重复的测量设计来确定这种综合征潜在的视觉空间和社会情绪改变的神经异常的发展轨迹和基因剂量-反应特征。这方面的初步概念验证分析已经成功。尽管数据积累需要多年的谨慎和协调努力才能完成，但这些研究揭示基因对大脑发育的贡献的潜力是巨大的。 本工作包括以下研究：NCT01132885、NCT00004571、NCT00001258

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