# Genetic epidemiology of rare and regulatory variants for metabolic traits

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $627,100

## Abstract

PROJECT SUMMARY
Genome-wide association studies (GWAS) have successfully identified genetic variants associated with
common, complex diseases and quantitative traits. In the Metabolic Syndrome in Men (METSIM) study of
10,197 well-characterized individuals, we identified novel loci and additional signals for metabolic traits related
to obesity, type 2 diabetes (T2D), and the metabolic syndrome. However, most of the underlying genes, their
directions of effect, and mechanisms of action remain unknown. Subcutaneous adipose tissue serves as a
buffering system for lipid energy balance and may play a protective role in metabolic risk. Initial gene
expression data in subcutaneous adipose tissue from METSIM participants identified expression quantitative
trait loci (eQTLs) coincident with GWAS signals that suggest new candidate genes at dozens of loci. A more
thorough understanding of genetic influences on subcutaneous adipose expression variation would identify
additional target genes, especially for insulin resistance traits including waist-hip ratio (WHR), lipids, and T2D.
Further identifying genetic influences on chromatin variation in adipose tissue would help define molecular
events that influence regulatory mechanisms. Our overall goal is to identify the functional variants, target
genes, and mechanisms responsible for metabolic trait association signals. We hypothesize that examining
regulatory variants in a disease-relevant tissue and a large population cohort will reveal genes and
mechanisms for obesity, T2D, and metabolic syndrome.
In the next phase of this study, we will identify allelic differences in subcutaneous adipose tissue gene
expression and chromatin accessibility in an expanded analysis of METSIM samples. We will detect variants
associated with expression, splicing, and chromatin accessibility and use the data to annotate new and existing
metabolic trait-associated signals. We will perform mediation analyses to identify variants that act on traits via
changes in chromatin accessibility and/or expression, and we will further investigate changes in chromatin
accessibility or gene expression that interact with insulin resistance status. Finally, we will test variants for
effects on transcriptional activity and transcription factor binding, and determine the effects on gene expression
by deleting or activating regulatory elements in a human adipocyte cell strain. Excellent human tissue and
clinical resources, technological advances in high-throughput sequencing, and advanced analysis methods
make this project timely and feasible. Through this work we expect to identify novel genes for metabolic traits,
discover pathogenic regulatory variants, and learn how environmental context can influence the dynamic range
of gene regulation and the development of disease. Better understanding of these factors and mechanisms
may lead to improved diagnoses and treatments for obesity, T2D, and metabolic syndrome.

## Key facts

- **NIH application ID:** 10149989
- **Project number:** 5R01DK093757-10
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** KAREN L. MOHLKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $627,100
- **Award type:** 5
- **Project period:** 2011-09-05 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149989

## Citation

> US National Institutes of Health, RePORTER application 10149989, Genetic epidemiology of rare and regulatory variants for metabolic traits (5R01DK093757-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149989. Licensed CC0.

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