# Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $684,141

## Abstract

Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease
Summary
Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation),
affects up to 29 million adults in the U.S. and has become the leading cause of liver disease.
NAFLD can lead to liver cirrhosis and hepatocellular carcinoma. There are few effective ways to
prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its
diagnosis and treatment. NAFLD is heritable (genetically influenced) and identified common
variants that explain ~20% of heritability of this trait, suggesting that more causal variants that
affect this trait remain to be discovered. While histology has historically been used to define
NAFLD steatosis, NAFLD is now routinely diagnosed using non invasive imaging or elevated
ALT/AST without the presence of other liver diseases. We recently published the world’s largest
cross ancestry GWAS analysis of serum ALT/AST/ALP GWAS where we identified >300
genome wide significant variants that associate with these traits; 23 of them also associated
with increased hepatic steatosis assessed in 7600 individuals using liver imaging. We showed
that a polygenic risk score (PRS) from the ALT but not AST or ALP genome wide significant
variants was able to predict steatosis, cirrhosis, and HCC. Here, we have assembled the largest
collection of multiethnic samples with hepatic steatosis measured with liver imaging or NAFLD
diagnosed by international classification of disease code with genome wide data also available.
We hypothesize that (1) common and low frequency variants contribute to NAFLD variation and
risk (2) identified variants in aggregate will improve risk prediction for liver steatosis, cirrhosis
and HCC compared to single variants and (3) GWAS NAFLD prioritized genes, when targeted,
will function autonomously in hepatocytes to cause steatosis. The objective of this application is
to carry out a GWAS meta analysis of NAFLD across imaging or ICD diagnosed NAFLD. A PRS
will be created from verified NAFLD associated variants effect and assessed for its ability to
predict, steatosis, cirrhosis, HCC. We will annotate verified NAFLD associated variants to
identify target genes for follow up functional studies for effects on steatosis alone and in
combination. Results from this work will help define the genetic and metabolic mechanisms that
cause NAFLD and inform development of new biomarkers as well as potential therapeutics for
this condition.

## Key facts

- **NIH application ID:** 10465360
- **Project number:** 1R01DK131787-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Elizabeth K Speliotes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $684,141
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465360

## Citation

> US National Institutes of Health, RePORTER application 10465360, Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease (1R01DK131787-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465360. Licensed CC0.

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