# Integrated omics analysis of clonal hematopoiesis and cardiovascular disease risk in TOPMed

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $624,385

## Abstract

PROJECT SUMMARY
Clonal hematopoiesis of indeterminate potential (CHIP) involves the gain of somatic mutations that confer a
selective advantage to hematopoietic stem cells and lead to the expansion of a clonal population of blood cells.
CHIP is common in older individuals and is associated with increased risk of blood cancers and atherosclerotic
cardiovascular disease (ASCVD). Genes commonly mutated in CHIP include known regulators of DNA
methylation (DNAm) and RNA splicing. In this application, we propose to take advantage of a novel omics data
resource being generated by the TOPMed program to investigate the roles of DNAm, gene expression, and
differential splicing as mechanisms potentially mediating the relationship between CHIP and risk for ASCVD. In
Aim 1 we will use genome-wide DNAm and RNA-seq data collected from blood samples of tens of thousands of
individuals to investigate whether methylomic and transcriptomic patterns differ in individuals with CHIP. We will
consider individual genes and subsets of the genes most commonly mutated in CHIP separately, since each of
these genes is likely to have different functional consequences given their different regulatory roles. In Aim 2,
we will test for the presence of CHIP-associated methylomic and transcriptomic differences that are driven by
specific immune cell types. In Aim 3, we will use Mendelian randomization to identify CpG sites or genes that
may causally mediate the relationship between CHIP mutations and ASCVD risk. In Aim 4, we will integrate the
multiple omics data in a biologically informed deep learning model to investigate how CHIP mutations and
methylomic and transcriptomic changes may collectively contribute to risk for ASCVD and identify key biological
processes through which these changes influence disease risk. By characterizing the epigenomic and
transcriptomic consequences of CHIP mutations in specific genes and within specific cell types and examining
the potential of TOPMed trans-omic data to predict disease risk, this work will advance current understanding of
CHIP and risk for ASCVD.

## Key facts

- **NIH application ID:** 10890887
- **Project number:** 5R01HL168894-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Karen Conneely
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $624,385
- **Award type:** 5
- **Project period:** 2023-07-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890887

## Citation

> US National Institutes of Health, RePORTER application 10890887, Integrated omics analysis of clonal hematopoiesis and cardiovascular disease risk in TOPMed (5R01HL168894-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890887. Licensed CC0.

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