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

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $1,278,748

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10539615
- **Project number:** 1R01MH131296-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** RONALD P HART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,278,748
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539615

## Citation

> US National Institutes of Health, RePORTER application 10539615, Cellular consequences and convergent biology of schizophrenia-associated rare variants in the diverse GPC cohort (1R01MH131296-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10539615. Licensed CC0.

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