# Quantifying the relationship between 3D genome structure and the genetic architecture of common complex disease

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $30,747

## Abstract

PROJECT SUMMARY/ABSTRACT
The three-dimensional (3D) conformation of the genome plays an integral role in regulating gene expression.
The genome folds into megabase-long topologically associating domains (TADs), regions that self-interact, but
rarely contact regions outside the domain. TADs modulate gene regulation by restricting interactions of
regulatory elements, like enhancers, to their target genes. Disruption of the insulating boundaries between
TADs by large-scale rare variants can cause severe developmental phenotypes. However, the relationship
between the genetic basis underlying common phenotypes and 3D genome architecture across different
cell-types is not understood. Common small-scale (e.g. SNP) variation may change 3D genome structure in a
cell-type-specific manner, leading to changes in gene expression and disease risk. As genome-wide
association studies (GWAS) become more common, cell-type-specific interpretation of disease-associated
variants is essential for mechanistic understanding of disease. This work will examine variation in different 3D
contexts across diverse cell-types, quantifying their evolutionary constraint and contribution to common
phenotypes. I hypothesize that genetic variation at TAD boundaries contributes more to the burden of
common disease than variation in TADs. Furthermore, I hypothesize that disruption of cell-type-specific TAD
boundaries contributes to diseases in relevant cell-types. First, 37 cross-cell-type and four cross-species 3D
genome maps will be integrated to measure 3D element functional conservation. Comparing different 3D
contexts (i.e. TADs and boundaries) across cell-types and species will provide a framework for integrating 3D
genome maps into interpretation of disease-associated variants. Second, the relationship between 3D
architecture and the genetic architecture of 28 common complex traits will be mapped through partitioned
heritability analysis. This will reveal if TAD boundaries have a greater genetic contribution to different common
diseases than TADs. Third, cell-type-specific 3D elements will be assessed for cell-type-specific functional
effects through enrichment analyses of existing functional annotations and biobank data. This work will enable
cell-type-specific and 3D structural-aware variant interpretation by quantifying the relationship between the
genetic architecture of disease and 3D genome structure. Furthermore, this project, when combined with
rigorous clinical and scientific training, will provide opportunity for interdisciplinary collaboration with experts
and mastery of multiple techniques in human genetics, well-equipping me to become a physician-scientist
leader in genetics.

## Key facts

- **NIH application ID:** 10179367
- **Project number:** 5F30HG011200-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Evonne McArthur
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,747
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179367

## Citation

> US National Institutes of Health, RePORTER application 10179367, Quantifying the relationship between 3D genome structure and the genetic architecture of common complex disease (5F30HG011200-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10179367. Licensed CC0.

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