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: 10929820
• 负责人: Karen FAITH Berman
• 金额: $ 170.45万
• 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/10929820
• 关键词: 7q11.23; Adult; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Aorta; Aortic Valve Stenosis; Area; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; Cell Line; Cell physiology; Cells; Cellular Morphology; Cerebellum; Characteristics; Child; Childhood; Chromosome 7; Clinical; Cognition; Complement; Complex; Copy Number Polymorphism; DNA; Data; Data Collection; Dedications; Development; Developmental Anatomy; Diffusion Magnetic Resonance Imaging; Disease; Dose; Emotional; Equation; Face; Fiber; Fright; Functional Magnetic Resonance Imaging; Gene Dosage; Gene Mutation; General Population; Genes; Genetic; Genetic Determinism; Genomic Segment; Genotype; Handedness; Haploidy; Haplotypes; Heterogeneity; Incidence; Individual; Insula of Reil; Judgment; Knowledge; LIMK1 gene; Lead; Life; Link; Literature; Live Birth; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Methodology; Methods; Modeling; Molecular Abnormality; Multimodal Imaging; Mutation; Nature; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosecretory Systems; Parietal; Participant; Pathology; Pattern; Personality; Persons; Phenotype; Play; Population Characteristics; Positron-Emission Tomography; Rare Diseases; Regression Analysis; Regulation; Rest; Role; SNP array; SNP genotyping; Sampling; Seminal; Series; Siblings; Single Nucleotide Polymorphism; Social Behavior; Social Network; Stimulus; Structure; Surface; Syndrome; System; Techniques; Testing; Tissues; Translating; Variant; Veins; Visual; Visuospatial; Williams Syndrome; Work; autism spectrum disorder; behavioral phenotyping; boys; brain size; clinical predictors; clinically relevant; cognitive function; cohort; connectome; design; emerging adult; experience; experimental study; gene function; genome wide association study; gray matter; human model; in vivo; indexing; induced pluripotent stem cell; intraparietal sulcus; microdeletion; morphometry; multimodal neuroimaging; myelination; neural; neural circuit; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatric disorder; novel; pain sensitivity; pubertal timing; response; sex; social; social cognition; social influence; success; transcriptome sequencing; 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, associated neural fiber tract anomalies, and altered functional connectivity with other brain regions. 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. Further collaborative efforts this year have also begun to establish induced pluripotent stem cell lines from individuals with WS and Dup7 and their unaffected siblings, with a plan to differentiate these pluripotent cells into lab-grown neurons that can provide neural tissue from living individuals. 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. Additional work has been focused on uncovering neural mechanisms linking 7q11.23 copy number variation with pubertal timing, which is early in people with WS. Specifically, we are examining pubertal milestones and neuroendocrine anatomical developmental metrics as a function of gene-dosage (WS<TD<Dup7). This work incorporates genome wide association and RNAseq data to investigate specific genetic candidates that may be particularly relevant pubertal developmental drivers. Additional collaborative work this year has been dedicated to better understanding pain sensitivity phenotypes in 7q11.23 CNVs through both clinical and basic methods. 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 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. Additionally, we identified that LIMK1 plays an important role in the structure and function of the intraparietal sulcus. Here, we confirmed that structural and functional deficits in the intraparietal sulcus are present in children with WS and persisted longitudinally into early adulthood, and further showed that LIMK1 haplotype variation was associated with intraparietal sulcus structure in a large sample of typically developing children and healthy adults. Altogether, 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, and identifies LIMK1 as an important gene in the normal development of the intraparietal sulcus and in the WS phenotype. 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 longitudinal study 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

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).这些研究负责阐述7q11.23表型的视觉空间和社会情感方面的神经基础。通过多种神经影像学技术，包括基于体素和表面的皮质形态法，扩散张量成像，功能性MRI，我们确定WS中的视觉空间构造缺陷与收敛的伴随性内部硫sus孔的变化有关。具体而言，在这个大脑区域中，我们已经表明，WS的个体携带神经完整性中断，空间判断过程中的激活改变，灰质体积和沟深度降低，相关的神经纤维道异常以及与其他大脑区域的功能连接改变。同样，在追求系统级的相关性和WS中观察到的非社交焦虑的相关性时，我们发现杏仁核激活减少了，通过查看具有恐惧的含量的面孔的图片，相反，杏仁核引起了杏仁核的响应，并增加了杏仁核对非社交恐怖图片的反应增加，这些图片对非社交图片的响应，这些图片链接到更改的模型，以构建与更改的形式相关化。我们还确定了预测特征WS个性的前岛结构，功能和区域间连通性的收敛变化。今年的努力集中在数据收集的数据收集数据，对视觉空间和社会情感系统的完整性进行了相同的结构和功能测量，并具有额外的体内神经成像测量，对骨髓的骨髓化测量，越来越多的儿童越来越多，有和没有WS关键区域拷贝数变化的儿童（即，在WS中具有较大的一个人（即，在典型的TD）中有一个型号的型号（即，均具有较长的型号）。 WS神经发育计划。今年的进一步合作努力也开始开始建立来自WS和DUP7及其未受影响的兄弟姐妹的个体的诱导多能干细胞系，并计划将这些多能细胞区分为实验室成长的神经元，这些神经元可以提供可提供神经组织与活人的神经组织。 在旨在建立神经结构基因剂效应的概念验证工作中，我们发现了总体大脑大小的增加（DUP7> TD> WS），但相对小脑大小（WS> TD> DUP7）降低了受影响基因的拷贝数。有趣的是，这两种DUP7表型（大脑大小和相对较小的小脑）都在自闭症文献中，尤其是在男孩中进行了描述，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中更局部形态计量法以及局部旋转指数和静止状态全脑连接性进行类似的基因剂量分析，而后者则使用连接范围范围的关联研究方法以及独立的组件和双重回归分析。 额外的工作集中在发现将7q11.23拷贝数变化与青春期时机联系起来的神经机制，这是WS患者的早期。具体而言，我们正在研究青春期里程碑和神经内分泌的解剖学发育指标随基因剂量的函数（WS <TD <dup7）。这项工作结合了基因组广泛的关联和RNASEQ数据，以研究可能特别相关的青春期发展驱动因素的特定遗传候选者。今年的其他协作工作已致力于更好地理解7q11.23 CNV中通过临床和基本方法的疼痛敏感性表型。 为了了解威廉姆斯综合征基因组区域拷贝数变化的个体的异质性，我们启动了对染色体区域的剩余（WS）或重复的（WS）或重复的（DUP7）中单核苷酸多态性和遗传单倍型的影响的研究。我们开发了新的方法来从SNP-CHIP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，以测试以下假设：ELN基因的常见变异（而不是其他7Q11.23基因）可以预测主动脉结构的临床意义异常。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，并确定与WS参与者中主动脉狭窄相关的单个核苷酸多态性，并保护DUP7参与者中主动脉膨胀。正在进行的工作将集中于理解WS区域内的序列变化如何易于神经表型的变异性，例如我们观察到的上述宏观结构特征与7Q11.23拷贝数变化相关，以基因剂量依赖的方式相关。 来自WS发育队列的初步数据表明，在视觉空间挑战期间，在社会显着刺激的处理过程中的社交网络激活发生了改变，这与假设的假设是在早期生命中植根于WS的假设。最近，在这个队列中，我们发现了WS中腔内沟内功能连接性的非典型模式，这些模式的功能降低了与视觉网络的合作性，但相反，社交大脑网络链接增强了。此外，我们确定Limk1在腔内沟的结构和功能中起重要作用。在这里，我们证实了WS的儿童存在于膜内沟中的结构和功能缺陷，并持续纵向直至成年早期，进一步表明Limk1单倍型的变化与大型典型发育中的儿童和健康的成年人和健康的成年人和健康的成年人中的毛内沟结构有关。 总的来说，这项工作提供了基于神经电路的观点，即这些多样化的视觉空间和社交电路如何在7q11复制变化以及该人群的行为特征的背景下整合，并将Limk1视为肠内沟的正常发展的重要基因，并在WS现象中识别出正常的基因。 总体而言，该项目不仅旨在扩大儿童中与WS相关的大脑系统的了解，而且还旨在确定这种综合征使用长期，重复的测量设计的神经异常和社会情感变化的神经异常和社会情感变化的神经异常和社会情感变化的神经异常的特征。这种静脉的初步概念验证分析已经成功。尽管数据应计算需要多年的仔细和一致的纵向研究才能完成，但是这些研究的潜力使对脑发育的遗传贡献前所未有。 这项工作包括以下研究：NCT01132885，NCT00004571，NCT0000001258

项目成果

Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli.

• DOI: 10.1038/tp.2015.98
• 发表时间: 2015-08-18
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Jabbi M;Chen Q;Turner N;Kohn P;White M;Kippenhan JS;Dickinson D;Kolachana B;Mattay V;Weinberger DR;Berman KF
• 通讯作者: Berman KF

Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain.

• DOI: 10.1038/s41598-017-06587-0
• 发表时间: 2017-07-24
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gregory MD;Kippenhan JS;Eisenberg DP;Kohn PD;Dickinson D;Mattay VS;Chen Q;Weinberger DR;Saad ZS;Berman KF
• 通讯作者: Berman KF

Bridging the gene-behavior divide through neuroimaging deletion syndromes: Velocardiofacial (22q11.2 Deletion) and Williams (7q11.23 Deletion) syndromes.

• DOI: 10.1016/j.neuroimage.2010.02.070
• 发表时间: 2010-11-15
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Eisenberg, Daniel Paul;Jabbi, Mbemba;Berman, Karen Faith
• 通讯作者: Berman, Karen Faith

Beyond linearity in neuroimaging: Capturing nonlinear relationships with application to longitudinal studies.

• DOI: 10.1016/j.neuroimage.2021.117891
• 发表时间: 2021-06
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Chen G;Nash TA;Cole KM;Kohn PD;Wei SM;Gregory MD;Eisenberg DP;Cox RW;Berman KF;Shane Kippenhan J
• 通讯作者: Shane Kippenhan J