# Systematic Functional Interpretation of Regulatory Variants in Neuropsychiatric Disorders

> **NIH NIH R01** · ENDEAVOR HEALTH CLINICAL OPERATIONS · 2021 · $806,037

## Abstract

ABSTRACT
Despite the mounting risk loci in genome-wide association studies (GWAS) of neuropsychiatric disorders,
identifying the causal variants/genes has been challenging, which hinders the translation of GWAS findings
into novel disease biology. A major hurdle is that most risk variants lie in noncoding regions of DNA without
easily interpretable function. Noncoding regulatory sequences often reside in open chromatin regions (OCRs).
With human induced pluripotent stem cell (hiPSC) neurons as a model in our initial productive R01 period, we
have identified abundant regulatory variants in OCRs that affect chromatin accessibility, exhibiting allele-
specific open chromatin (ASoC). ASoC SNPs frequently affect gene expression and are strongly enriched for
schizophrenia risk variants. However, most causal variants/genes of schizophrenia and other neuropsychiatric
disorders remain unknown. Because regulatory variants often act in specific biological context, e.g., cellular
stimulation or perturbation, we hypothesize that many neuropsychiatric disease variants may alter chromatin
accessibility and gene expression only in activated neurons. Various neuronal stimuli cause membrane
depolarization, resulting in robust activity-dependent chromatin and expression changes in mouse neurons.
Our pilot data in KCl-depolarized human neurons also showed substantial activity-dependent chromatin and
expression changes, notably, with hundreds of activity-dependent ASoC SNPs some of which are
schizophrenia risk variants. Leveraging the tractable hiPSC model that can be perturbed in the context of
genetic variation, this competitive renewal application will address three specific questions: (1) To what extent
genetic variation influences neural activity-dependent chromatin accessibility and gene expression? For this,
we will assay cell type-specific chromatin and expression at single-cell resolution in both baseline and
activated neurons of a well-powered hiPSC cohort, and perform quantitative trait loci (QTL) mapping to identify
activity-dependent ASoC and expression QTL (eQTL). (2) What is the contribution of activity-dependent
regulatory variants to neuropsychiatric disorders? For this, we will jointly analyze ASoC and eQTL SNPs with
neuropsychiatric GWAS datasets to fine-map causal disease variants that affect activity-dependent chromatin
and expression, followed by a multiplex CRISPR base editing to validate their function and cis-target genes. (3)
What is the mechanism of activity-dependent chromatin changes? For this, we will examine whether activity-
dependent chromatin regions are enriched for specific transcriptional factors (TFs), and explore the effects of
CRISPR-editing of TFs on chromatin accessibility, expression, and cellular phenotypes in human neurons. This
study will yield novel mechanistic insights into the contribution of neural activity-dependent chromatin and
expression changes to neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10210575
- **Project number:** 2R01MH106575-06
- **Recipient organization:** ENDEAVOR HEALTH CLINICAL OPERATIONS
- **Principal Investigator:** Jubao Duan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $806,037
- **Award type:** 2
- **Project period:** 2016-05-04 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210575

## Citation

> US National Institutes of Health, RePORTER application 10210575, Systematic Functional Interpretation of Regulatory Variants in Neuropsychiatric Disorders (2R01MH106575-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210575. Licensed CC0.

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