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异的个体进行一系列正在进行的多模态神经影像学研究（该位点的半合子微缺失或DNA连续片段的重复），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层形态测量、弥散张量成像和功能性MRI，我们已经确定WS的视觉空间构建缺陷与会聚性顶叶内沟改变有关。具体来说，在这一脑区，我们已经表明患有WS的个体神经完整性被破坏，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。同样地，在探究WS患者的超社交性和非社交性焦虑的系统层面相关性时，我们发现，观看含有恐惧内容的人脸图片会导致杏仁核激活减少，相反，杏仁核对非社交性恐怖图片的反应会增加，这种异常与结构方程模型中前额叶调节的改变有关。我们还发现了脑岛前部结构、功能和区域间连通性的收敛性改变，这些改变可以预测WS人格的特征。作为我们的纵向WS神经发育计划的一部分，今年的工作重点是在越来越多的有和没有WS关键区域拷贝数变异的儿童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，一个WS个体，两个典型发展的TD个体，或三个受影响基因的Dup7拷贝）。