Multimodal Neuroimaging of Gene-Brain Relationships with a Focus on Williams Syndrome and 7q11.23 Duplication Syndrome

National Institute Of Mental Health

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Abstract

Our group 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 [in WS] or duplication [Dup7] 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 copy number 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 exhibit 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 statistical structural equation models. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity that predict the characteristic WS personality. In our longitudinal WS neurodevelopmental initiative, we have focused on data collection of these same structural and functional measurements of visuospatial and socio-emotional systems neural integrity, with additional in vivo neuroimaging measurements of myelination to understand brain maturational processes under different 7q11.23 gene dosage contexts. Further collaborative efforts this year have also expanded the study of induced pluripotent stem cell lines from individuals with WS and Dup7 and their unaffected siblings, and we have begun 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 > typically developing > WS) but decreasing relative cerebellar size (WS > typically developing > 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. We have also focused on uncovering neural mechanisms linking 7q11.23 copy number variation with pubertal timing, which is early in people with WS and late in people with Dup7. Specifically, we have shown that gene-dosage (WS<TD<Dup7) strongly influences girls’ age at menarche and shapes the trajectory of pituitary gland growth. This work incorporated large-scale genome wide association and RNAseq data resources to investigate specific genetic candidates that may be particularly relevant pubertal developmental drivers. We have dedicated additional collaborative work to better understanding pain sensitivity phenotypes in Dup7 through both clinical and basic methods, discovering evidence that the STX1A gene may play a strong role in the “genetic analgesia” that is common in Dup7, and potentially pointing to previously untargeted routes to pain control. 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 elastin [ELN] gene predicts clinically meaningful abnormalities of aortic structure (supravalvar aortic stenosis in WS, but aortic dilations of aneurism in Dup7). 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 DNA 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. In children and adolescents from our WS developmental cohort, we have now shown that 7q11.23 genetic variation, specifically hemideletion, predisposes to alterations in neural functioning across visuospatial and social domains in a manner predicted by our previous work. Specifically, we demonstrated reduced engagement of the bilateral intraparietal sulcus in children with WS during visuospatial processing, but increased activation in the bilateral fusiform gyri in response to face stimuli, consistent with the hypothesis that such visuospatial and social neurobiological differences are rooted early in life. Furthermore, we have now demonstrated that this predisposition is largely invariant to various cognitive task demands. In this cohort, we have uncovered atypical patterns of intraparietal sulcus functional connectivity in WS, including diminished cooperativity with visual networks but, in contrast, enhanced social brain network cooperativity. 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. Together, 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 trajectories (throughout childhood) and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in these syndromes using a longitudinal, repeated measures design. Preliminary proof-of-concept analyses in this vein have already been successful. 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