# Systematic in vivo characterization of disease-associated regulatory variants

> **NIH NIH UM1** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $924,412

## Abstract

ABSTRACT
Thousands of genetic loci are associated with human traits or disease risk, and these loci each typically contain
tens to hundreds of variants, most of which are non-coding and lack direct evidence of effects on genes.
Experimental tests of genomic variants are needed to identify functional effects, which can be specific to one
sex, tissue, and/or perturbed environmental context. Testing effects of risk variants on gene regulation requires
an ability to quantify the potentially modest consequences of thousands of alleles in a carefully controlled study.
Our overarching goal is to systematically characterize the impact of human genetic variation on gene regulation
via massively parallel reporter assays (MPRA). We will select variants based primarily on genome-wide
association studies (GWAS) for common diseases and complex traits relevant to the brain, liver, lung, muscle,
and/or heart. We will examine all plausible functional candidates at prioritized GWAS loci to provide data for tests
of regulatory variant prediction algorithms, positive control variants, and variants prioritized based on regulatory
element annotations. The gene regulatory effect of ~500,000 variant alleles will be interrogated in five organs
(brain, liver, lung, muscle and heart) using systemic circulation of adeno-associated viral (AAV) MPRA libraries.
We will repeat this experiment in a perturbed inflammatory state to evaluate gene-environment interactions. As
a result, we will comprehensively characterize variant effects on regulatory function by analyses of variants in
the physiological conditions of multiple tissues, in both sexes, with and without perturbation typical of disease
environments. Selected variants will be edited into human pluripotent cells for validation. As members of the
Impact of Genomic Variation on Function (IGVF) Consortium, we will generate a regulatory variant catalog for
the community, and enable future studies through data collection and predictive models. Successful completion
of these aims will provide ~10 million allelic effect data points that encompass tissue-, sex-, and perturbation-
specific regulatory effects. We will work with the IGVF consortium to finalize selection of variants, organs, and
perturbations to generate a comprehensive catalog. The expertise of the study investigators in GWAS, statistical
and computational genetics, human genomics, AAV delivery, and mouse physiology make achievement of these
aims feasible and likely highly informative to understand how genomic variation impacts human health and
disease.

## Key facts

- **NIH application ID:** 10296745
- **Project number:** 1UM1HG012003-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michael Isaiah Love
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $924,412
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296745

## Citation

> US National Institutes of Health, RePORTER application 10296745, Systematic in vivo characterization of disease-associated regulatory variants (1UM1HG012003-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10296745. Licensed CC0.

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