# Identifying functional variants in COPD GWAS loci

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $848,038

## Abstract

Project Summary
The identification of novel susceptibility genes for complex diseases like COPD could transform our
understanding of disease pathophysiology and provide new targets for treatment. The primary goals of this
project are to identify the functional genetic variants within five well-established COPD GWAS loci; to identify
the key genes influenced by these functional variants; and to assess the impact of these key genes and
functional genetic variants on COPD pathogenesis. In recent collaborative GWAS through the International
COPD Genetics Consortium, we found 22 genomic loci associated with COPD at genome-wide significance.
We will focus our studies in this proposal on five of these COPD GWAS loci that include multiple candidate
genes and for which a likely functional variant has not been identified. We hypothesize that an integrated
approach that utilizes whole genome sequencing for fine mapping, gene expression data, bioinformatic
approaches, and new laboratory assessments will enable the identification of the key genes and functional
variants within these five COPD GWAS loci. Moreover, we hypothesize that focused cell-based studies of
these key genes and their functional variants will provide novel insights into COPD pathogenesis. To address
these hypotheses, we will start by identifying functional variants within these five loci using massively parallel
reporter assays in multiple cell types, bioinformatic approaches with public and recently generated Omics data,
and genetic association analysis. We will then determine which gene or genes are influenced by these
functional variants by performing chromosome conformation capture (4C-Seq), confirming the regulatory
effects of the functional variants on the endogenous promoter of the implicated gene, and demonstrating
effects on gene expression of the implicated gene by gene editing the regulatory region using CRISP-Cas9
approaches. Finally, we will use cellular models to determine the effects of inactivating the key gene and its
functional variants on COPD-related read-outs of cell death, apoptosis, and cell activation. To accomplish
these goals, a unique and highly integrated approach combining genetic association analysis, molecular
studies of regulatory elements, and functional cell-based assays has been developed that will likely provide
important insights into COPD pathogenesis.

## Key facts

- **NIH application ID:** 9939680
- **Project number:** 5R01HL137927-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL H. CHO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $848,038
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939680

## Citation

> US National Institutes of Health, RePORTER application 9939680, Identifying functional variants in COPD GWAS loci (5R01HL137927-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939680. Licensed CC0.

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