Mapping functional brain connectivity, neurodevelopment, and imaging-genetic associations in individuals with genetic and clinical risk factors for neuropsychiatric illness

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PROJECT SUMMARY In neurodevelopmental disorders such as schizophrenia (SCZ), genetic and environmental factors converge on disrupted brain development and function. One way that we can gain more clarity on the relationships between genes, neural systems, and symptoms is through considering rare genetic conditions with large effects on brain development. 22q11.2 Deletion Syndrome (22qDel) is a recurrent copy number variant (CNV) in which a hemizygous deletion of ~2.6 Mb of genetic material (~46 protein-coding genes) from chromosome 22 causes a neurodevelopmental phenotype with a ~25% risk of psychotic illness and increased rates of ASD, intellectual disability, attention deficit and anxiety disorders. Studying individuals with 22qDel can therefore provide an impactful translational model and ‘genetics-first’ framework for understanding the complex biological pathways underlying disabling conditions like SCZ. The proposed research plan seeks to map convergent and divergent brain connectivity disruptions in 22qDel and in individuals at Clinical High Risk (CHR) for developing psychosis spectrum disorders relative to typically developing (TD) controls. To this end, we will make use of the largest multi-site sample collected to date of longitudinal resting-state fMRI from 22qDel (n=217) and matched controls (n=149), along with data from the North American Prodrome Longitudinal Study (NAPLS) with CHR (n=318) and TD (n=206). We will also apply spatial transcriptomic data from the Allen Human Brain Atlas (AHBA) to test relationships between fMRI biomarkers and typical spatial patterns of gene expression in the brain. Specifically, our aims are to: (i) Test the hypothesis that functional connectivity disruptions in individuals with genetic and clinical risk factors for psychosis converge on brain-wide sensory and executive networks, (ii) Test the hypothesis that 22qDel and CHR will exhibit convergent disruptions in functional connectivity development across the age range relative to TD controls, and that individual deviations from typical trajectories will predict psychosis symptoms, and (iii) Test the hypothesis that spatial patterns of resting-state fMRI disruptions in 22qDel are related to spatial gradients of inhibitory and excitatory neuronal gene expression in post-mortem brain tissue from typical adults. This multimodal approach aims to elucidate brain biomarkers and neurobiological mechanisms related to genetic and clinical risk factors for psychosis spectrum disorders. To facilitate this research, the proposed training plan includes coursework, workshops, and professional development activities related to analysis of multi-site data, longitudinal data analysis, neurogenetics, and science communication. The Bearden Lab and Neuroscience Interdepartmental Program at the University of California Los Angeles will provide the ideal academic environment for the proposed training and research plan.