# Discovery and validation of genetic variation impacting the gene regulatory landscape during human cortical development

> **NIH NIH U01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $615,491

## Abstract

The vast majority of common genetic variation underlying risk for neuropsychiatric disorders 
resides in poorly annotated non-coding regions of the genome and likely impacts the regulation of 
gene expression. In order to move from a location in the genome associated with risk to a 
regulatory mechanism, there are several major gaps in knowledge including: (a) the causal 
variant(s) within the associated locus, (b) the regulatory elements impacted by those causal 
variant(s), (c) the cell-type(s) and developmental time period(s) at which the causal variants(s) 
exert their effects, and (d) the gene(s) impacted by those causal variant(s). In this proposal, we 
will identify genetic influences on two features of chromatin architecture (enhancer 
histone marks and their 30 interactions) during human cortical development in order to more 
completely explain regulatory mechanisms leading to risk for neuropsychiatric disorders. In a large 
population of post-mortem human developing cortical tissue that has previously undergone 
genome-wide genotyping and transcriptomic profiling, we will utilize a technique that 
allows us to simultaneously measure enhancer activity and its interaction profile 
(H3K27ac HiChIP). We will then identify genetic influences on these two features of chromatin and 
their co-localization with previous and growing neuropsychiatric disorder genome-wide association 
(GWAS) risk loci. Psychiatric disorder risk variants may exert their regulatory impact by (1) 
changing enhancers (H3K27ac QTLs or histone acetylation (ha)QTLs) and/or (2) chromatin 
interaction (interaction-QTLs). This novel class of QTLs will enhance our understanding of 
the molecular processes underlying human neurodevelopment and how that development is altered in 
neuropsychiatric disorders. Further, we will conduct two orthogonal methods to validate the impact 
of the genetic variants and assess their cell-type specificity. We will perform cell-type specific 
massively parallel reporter assays (MPRA) to validate the functional impact of haQTLs. In this 
assay, cloned oligos containing the enhancer associated alleles drive expression of barcoded 
transcripts that can be used to assess regulatory differences and identify causal variants. We 
will also apply a haplotype-specific chromatin imaging technique to visualize how regulatory 
variation impacts chromatin interactions in individual nuclei. This technique paints 
sections of each chromosome with allele-specific oligos in order to visualize and 
measure the physical interactions of the 0NA molecule. Completing the aims of this proposal will 
allow us to identify largely complete regulatory mechanisms impacting human brain development and 
risk for neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 9948273
- **Project number:** 1U01MH122509-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jason Louis Stein
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $615,491
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948273

## Citation

> US National Institutes of Health, RePORTER application 9948273, Discovery and validation of genetic variation impacting the gene regulatory landscape during human cortical development (1U01MH122509-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9948273. Licensed CC0.

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