# Cellular and developmental genetic regulation of 3' isoform diversity in the human brain and its contribution to neuropsychiatric disorders

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $718,662

## Abstract

PROJECT SUMMARY/ABSTRACT
As large-scale genome-wide association studies (GWAS) continue to yield now thousands of genomic loci
robustly associated with neurodevelopmental and psychiatric disorders, including autism spectrum disorder
(ASD) and schizophrenia (SCZ), the major defining challenge of the post-GWAS era is to characterize the
concrete biological mechanisms through which this polygenic variation confers disease risk, at scale. To this
end, we and others have recently developed methods and resources for systematic integration of GWAS results
with population-level functional genomic reference panels -- identifying isoform-regulation during the second
trimester of human brain development as mediating the greatest proportion of heritability across multiple
neuropsychiatric GWAS studies compared with earlier or postnatal timepoints. Yet, no studies have
characterized genetic regulation of alternative polyadenylation (APA) in the developing brain, a critical yet
understudied tissue-specific gene-regulatory mechanism with established roles in neuronal mRNA metabolism,
subcellular trafficking, and cellular differentiation. Our preliminary data indicates widespread dysregulation of
APA in stem-cell-based models and postmortem brain tissues from subjects with ASD and SCZ, as well an
outsized enrichment of psychiatric GWAS signal with APA quantitative trait loci (QTL) in the developing human
brain. This proposal seeks to integrate large-scale functional genomics, single-cell and long-read sequencing,
deep learning, and genome-editing in human neuronal stem-cell models to develop a detailed, mechanistic
understanding of APA regulation during human brain development and its contribution to neuropsychiatric
disorder pathophysiology. Specifically, we will generate a comprehensive atlas of APA regulation across
neurodevelopment, leveraging data from >3650 bulk tissue samples as well as single-nucleus RNAseq data
across >700 unique donors, including 170 with SCZ/ASD. We will train and validate a deep learning model
predicting APA changes from primary sequence. Through integration with psychiatric GWAS, we hypothesize
that APA regulation will provide substantially greater resolution to detect candidate biological mechanisms
underlying psychiatric GWAS loci. Finally, predicted SNP-UTR-disease mechanisms will be experimentally
tested via high-throughput screens and genome-engineering in iPSC-derived neurons. Together, these studies
will systematically characterize a critical, yet underexplored area of genomic regulation in the human brain across
development, thereby providing novel insights into psychiatric disease mechanisms and identifying potential
neurobiological targets for therapeutic development and intervention.

## Key facts

- **NIH application ID:** 10972737
- **Project number:** 1R01MH137578-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Gandal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $718,662
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10972737

## Citation

> US National Institutes of Health, RePORTER application 10972737, Cellular and developmental genetic regulation of 3' isoform diversity in the human brain and its contribution to neuropsychiatric disorders (1R01MH137578-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10972737. Licensed CC0.

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