Cellular consequences and convergent biology of schizophrenia-associated rare variants in the diverse GPC cohort

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Project Summary / Abstract Recent discoveries implicate specific genetic variants that confer extremely high risk for schizophrenia (SZ), a devastating psychiatric syndrome. Alongside these genetic discoveries there have been parallel advances in molecular neuroscience, including induced pluripotent stem (iPS) cell technology; high-throughput cellular technologies such as high content imaging and single cell genomics; and multiplex “cell village” approaches. These techniques allow for rigorous yet efficient interrogation of complex biological processes in previously inaccessible human neuronal cell types. The combination of genetic findings and technological advances are powerful tools for addressing what has become the “great white whale” of modern psychiatry: What is the underlying pathophysiology that gives rise to a SZ phenotype? We propose that high penetrance of rare SZ mutations derive from large effects at the molecular and cellular levels. We will identify downstream targets and pathways impacted by five rare SZ-associated variants with large effect sizes: deletions at chromosomal locations 2p16 (localized to the NRXN1 gene), 3q29, 15q13.3, 22q11.2, and duplication at 16p11. A key strength of this proposal is our access to the Genomic Psychiatry Cohort (GPC). Importantly, the GPC is a diverse cohort with significant representation of African ancestry. We will select for study previously-banked cryopreserved lymphocytes from individuals with SZ who carry one of these five defined variants (n=20 each genotype), prioritizing underrepresented minorities, to generate iPS cell lines. A clear advantage of the GPC is its large diverse control sample, allowing us to select controls (n=40) that are matched by genomic background to the SZ cases, increasing the rigor of our study. A consistent but surprising observation about these SZ-associated rare variants is their similarity in both effect size and phenotypic characteristics, giving rise to the hypothesis that these variants converge on downstream molecular targets and/or cellular pathways. We will test the hypothesis that SZ-associated rare mutations cause molecular perturbations in neurons at the level of chromatin accessibility and gene expression and that genes or pathways impacted by two or more of these SZ-associated variants converge, with more overlap than expected by chance. Finally, we will validate molecular pathways using multimodal cellular phenotypic levels of analysis. Identifying the specific biological processes that are disrupted by SZ-associated loci will open a window into the complex molecular biology of this disorder. The substrate for our mechanistic studies will include subjects with diverse genetic backgrounds that have been historically underrepresented in genetic studies, ensuring that our results are generalizable to these communities, who suffer disproportionately from adverse mental health outcomes. The tools and data generated herein will support the mental health field aligning with NIMH priorities, lead to transformative insights into the neurobiology of SZ, and uncover novel targets that may be a launch point for therapeutic discovery.