# Linking Psychiatric Genetics to Cell-Type Specific Enhancer Function

> **NIH NIH R01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2021 · $719,059

## Abstract

PROJECT SUMMARY
Genome-wide association studies (GWAS) provide robust statistical evidence linking individual sequence
variants to increased risk of disease. However, the majority of GWAS-identified risk variants identified to date,
including those for psychiatric disorders, do not affect protein-coding sequence but instead map to noncoding
DNA. GWAS alone yield little direct insight into the mechanisms by which these variants confer increased risk.
It is widely assumed that many affect the function of distant-acting transcriptional enhancers, but the
historically poor annotation of noncoding functional sequences in the human genome has rendered their
interpretation challenging. Over the past decade, our lab and others made substantial progress toward
identifying enhancers in the genome at scale. For example, our group has used ChIP-seq from mouse and
human brain tissues to identify initial collections of developmentally active brain enhancers. Furthermore, as
members of the ENCODE consortium, we generated the first high-resolution time series mapping the brain
chromatin landscape throughout mouse prenatal development. These resources, along with complementary
data from NIH-funded consortia, are now available to aid in the interpretation of GWAS results. Here we
propose to bridge the current gap between noncoding GWAS findings and mechanistic understanding
of psychiatric disorder etiology. We will couple extensive pre-existing epigenomic resources to
cutting-edge mouse engineering and single cell-resolution transcriptome analyses in order to
understand how enhancer variants contribute to psychiatric disease risk. Specifically we will: 1) Perform
an integrative analysis of psychiatric disorder GWAS results and epigenomically predicted brain enhancers to
identify regulatory sequences that harbor disease-associated variants and prioritize them for functional
validation, 2) Use high-throughput mouse transgenic assays to validate predicted enhancers in vivo and
determine the exact brain regions in which they are active, 3) Use single cell RNA-sequencing of transgenic
mice to determine the exact cell type(s) in which a brain enhancer functions, and 4) Use these in vivo
functional genomic methods to uncover whether and how disease-associated sequence variants impact the
cell type-specific activity of each enhancer. As whole genome sequencing of psychiatric disease cohorts
continues to progress, we will also assess variants from those studies. In combination, our work will uncover
how noncoding disease-associated variants alter enhancer function in vivo, link noncoding GWAS findings to
specific cell types, and provide a unique panel of well-characterized enhancers that can be used to label
discrete neuronal cell populations for further downstream characterization. The results will substantially
improve our mechanistic understanding of how noncoding sequence changes contribute to mental illness and
provide entry points for potential downstream therapies.

## Key facts

- **NIH application ID:** 10159963
- **Project number:** 5R01MH117106-04
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Axel Visel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $719,059
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159963

## Citation

> US National Institutes of Health, RePORTER application 10159963, Linking Psychiatric Genetics to Cell-Type Specific Enhancer Function (5R01MH117106-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159963. Licensed CC0.

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