Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), is a common disease that affects up to 29 million adults in the U.S., and will become the number one cause of liver disease worldwide by 2020. There are few effective ways to prevent or treat this disease. A better understanding of its etiology is needed to improve diagnosis and treatment. We previously found that NAFLD is heritable (genetically influenced) and identified common (minor allele frequency (MAF) >5%) single nucleotide polymorphisms (SNPs) at 5 loci that associate with hepatic steatosis first in ~7,000 individuals of European ancestry and then across ancestries. Variants at the 5 loci together explain ~20% of heritability suggesting that other influential variants remain to be discovered. We and others have now found that genes harboring functional coding (affecting protein sequence) common variants of small effect often can also harbor rare variants with large effects. At three of the five associated loci we have now identified putative functional coding variants across ancestries. Recent whole genome and exome sequencing studies identified many new coding variants but many are low frequency (MAF 1-5%) or rare (MAF < 1%) and neutral as opposed to damaging. These low frequency and rare variants have been underexplored in genome-wide association studies due to the limitations of imputation and small sample sizes. These variants can now be affordably assayed in large numbers of samples using the new Illumina Human Exome BeadChip. Further, we can test whether particular genes and variants affect hepatic lipid accumulation in a new cell based model of hepatic steatosis we have created. We hypothesize that low frequency (MAF 1-5%) and rare (MAF <1%) coding variants with effects on hepatic steatosis exist and if expressed in liver, affect liver lipid accumulation. To identify and characterize low and rare frequency variants for effects on NAFLD, we have now assembled the largest, most ancestrally diverse population based collection of individuals (>16,000 from 8 cohorts) with measures of hepatic steatosis and genotyped them with the Exome BeadChip. We will harmonize the hepatic steatosis phenotype and genotypes in our cohorts and carry out single variant, gene based, and conditional meta analyses across groups to identify putative causal variants. We will follow up top associating variants and genes from hepatic steatosis analyses in >4,000 histologically confirmed NAFLD cases and ~3,000 controls to replicate our findings. Using our cellular model of hepatic steatosis, we will overexpress and knockdown liver expressed genes harboring coding variants in human liver cell lines and characterize their genetic and lipidomic mechanisms of action. We will start with the three genes we have already identified that harbor coding variants that associate with NAFLD and then proceed to new genes identified and replicated from the proposed exome analyses. This work will begin to define the genetic and metabolic mechanisms which cause NAFLD to inform development of new biomarkers as well as potential therapeutics for this condition.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), is a common disease that affects up to 29 million adults in the U.S., and will become the number one cause of liver disease worldwide by 2020; ways to prevent or treat this disease are lacking due to poor understanding of its pathophysiology. Here we propose to use new resources and methods that we have developed to identify causal genetic NAFLD associating variants in the population and characterize their genetic and metabolic effects in a cell model of hepatic steatosis. Results from our work will help define the etiology of NAFLD and inform development of new biomarkers and potential therapeutics for this condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK106621-05
Application #
9700118
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Karp, Robert W
Project Start
2015-09-05
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2021-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Speliotes, Elizabeth K (2018) Thwart your destiny; effect of nonacoholic fatty liver disease genes on steatosis, liver injury and cirrhosis varies by body mass index. Hepatology 68:372-374
Maguire, Lillias H; Handelman, Samuel K; Du, Xiaomeng et al. (2018) Genome-wide association analyses identify 39 new susceptibility loci for diverticular disease. Nat Genet 50:1359-1365
Weinstein, Galit; Zelber-Sagi, Shira; Preis, Sarah R et al. (2018) Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study. JAMA Neurol 75:97-104
Teslovich, Tanya M; Kim, Daniel Seung; Yin, Xianyong et al. (2018) Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study. Hum Mol Genet 27:1664-1674
VanWagner, Lisa B; Khan, Sadiya S; Ning, Hongyan et al. (2018) Body mass index trajectories in young adulthood predict non-alcoholic fatty liver disease in middle age: The CARDIA cohort study. Liver Int 38:706-714
Gao, Chuan; Langefeld, Carl D; Ziegler, Julie T et al. (2018) Genome-Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex-Specific Adiposity Loci in Mexican Americans. Obesity (Silver Spring) 26:202-212
Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41
Liu, Dajiang J (see original citation for additional authors) (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 49:1758-1766
Fall, Tove; Mendelson, Michael; Speliotes, Elizabeth K (2017) Recent Advances in Human Genetics and Epigenetics of Adiposity: Pathway to Precision Medicine? Gastroenterology 152:1695-1706
Marouli, Eirini (see original citation for additional authors) (2017) Rare and low-frequency coding variants alter human adult height. Nature 542:186-190

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