# Integrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility Genes

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $732,482

## Abstract

SUMMARY
In 2019, ~100 million Americans were obese, fueling increases in obesity-related morbidity, mortality, and health
care costs, largely from cardiometabolic diseases (CMD). Large scale genetic studies have laid the foundation
for many downstream investigations into the pathogenesis of disease and the translation of this information into
public health applications. Over the last decade genome-wide association studies (GWAS) have substantially
improved our understanding of the genetic architecture of obesity related traits. The potential of these study
findings cannot be overstated for elucidating the biological or pathophysiological underpinnings of obesity and
its costly morbidities. Although GWAS on common variants have made strides in identifying > 1,000 signals
for obesity related traits, these studies are inherently limited without further translation into more actionable
findings. In this proposal, we will narrow association signals and map causal genes and pathways underlying
known obesity risk loci by applying innovative methods to integrate multiple OMICs (genOMICs,
epigenOMICs, transcriptOMICs and metabolOMICs). Additionally, we will explore the clinical relevance of
obesity susceptibility variants, genes, and pathways in a large BioBank linked to electronic health records (EHR)
to validate expected phenotypic associations and reveal novel phenotypic associations. Finally, we will conduct
in vitro functional studies of key variants and genes in physiologically relevant cells to reveal putative regulatory
mechanisms of variants and effects on metabolites and thus the underlying mechanisms critical to obesity
pathogenesis. Thus, in this proposal we leverage collaborations in the Cohorts for Heart and Aging Research in
Genomic Epidemiology (CHARGE), TransOMICs for Precision Medicine (TOPMed) Program, the Genome
Sequencing Project (GSP), and the EHR database from the Geisinger MyCODE Community Health Initiative
study (MyCode) to narrow in on genes underlying GWAS signals, perform clinical characterization, and
conduct in vitro functional studies to characterize the molecular underpinnings and biological
mechanisms of obesity-risk loci. Our approach will substantially move the field away from tag variants and loci
to causal variants, genes, and mechanisms. We anticipate that this work will generate fundamental and important
insights into the underlying etiology of obesity and ultimately point the way forward towards prevention and
treatment.

## Key facts

- **NIH application ID:** 10121960
- **Project number:** 1R01DK122503-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Anne Justice
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $732,482
- **Award type:** 1
- **Project period:** 2020-09-22 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121960

## Citation

> US National Institutes of Health, RePORTER application 10121960, Integrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility Genes (1R01DK122503-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10121960. Licensed CC0.

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