Wednesday, May 14, 2025
5/14/2025
Dissecting neural-immune mechanisms of psychosis and related neurodevelopmental disorders - Project Summary/Abstract Altered neural-immune (NI) gene expression has been observed in postmortem brain tissue from individuals with schizophrenia and other neurodevelopmental disorders. One mechanism by which NI function may affect the brain is through effects on neurite outgrowth and synaptic pruning during development; however, the effects of NI gene expression on in vivo brain development and behavior are not known. A major barrier to understanding how interindividual differences in NI expression relate to heterogeneous developmental trajectories is the inability to measure gene expression in the living human brain. Through a coordinated set of multimodal analyses, the current proposal aims to define the polygenic architecture of NI gene expression to generate a genome-wide resource for individual-level prediction and characterization of its impact on brain and behavioral trajectories in the pediatric population. Integrating functional genomic data from the PsychENCODE Consortium with several other large-scale resources, we will perform a multi-ancestry genome wide association study (GWAS) to identify the genetically regulated component of NI expression (GREx) in >4,000 human brain samples (Aim 1). Next, using genetics data in >11,000 multiethnic youth from the Adolescent Brain Cognitive Development (ABCD) Study, we will compute individual-level predictions of NI GREx and test the relationship with longitudinal trajectories of structural brain development (Aim 2). Finally, to examine how interindividual variability in NI GREx may relate to clinically-relevant symptomatology, we will test the relationship between NI GREx and age-related change in dimensional measures of mental health relevant to psychosis and other related neurodevelopmental disorders (Aim 3). By examining links between NI GREx and brain development in a large population- representative cohort of children, this project has the potential to inform our understanding of mental health as a continuous construct, and to aid in the prospective identification of individuals at heightened risk for psychosis and other psychiatric disorders. These aims are in-line with the NIMH strategic plan to define the brain mechanisms underlying complex behaviors, and to examine mental illness trajectories across the lifespan. The proposed research will take place at the University of California, Los Angeles (UCLA) under the mentorship of Drs. Daniel Geschwind, Carrie Bearden, Bodgan Pasaniuc, and Wesley Thompson, experts in functional genomics, psychosis spectrum disorders, computational genetics, and longitudinal statistical analyses, respectively. The proposed K01 will provide the PI with mentored research training in transcriptomics, including the analysis and interpretation of post-mortem human brain RNA-sequencing data, multi-ancestry GWAS, the neurobiology of psychosis, and statistical methods to model longitudinal data. This research and training will lay the foundation for the PI’s career development as a leading expert in the neurogenetic etiology of psychosis and pleiotropic psychiatric disorders. Results will support a future R01 extending this work into clinically ascertained populations and will elucidate the genetic mechanisms underlying neurodevelopmental heterogeneity in youth.
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