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  • Review Article
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Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology

Nature Reviews Gastroenterology & Hepatology volume 17, pages 40–52 (2020)Cite this article

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Abstract

Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.

Key points

  • Nonalcoholic fatty liver disease (NAFLD) is a liver disorder with high heritability, and no approved pharmacotherapy to date.

  • Although our understanding of the genetic underpinnings of NAFLD has advanced, known risk variants explain only a small fraction of heritability, suggesting the existence of ‘missing heritability’.

  • There is evidence for shared genetic modifiers and common pathophysiological pathways that link NAFLD, other liver diseases and related metabolic disorders.

  • Research has now progressed beyond genome-wide association studies (GWAS) to broader, causal and functional discovery via multi-trait GWAS, phenome-wide association studies (PheWAS), Mendelian randomization and functional annotation studies.

  • The next wave of genetic studies should have substantial translational implications for both drug discovery and personalization of medicine.

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Fig. 1: Schematic representation of a genome-wide association study and a phenome-wide association study.
Fig. 2: The pleiotropic effects of NAFLD risk loci.
Fig. 3: Schematic representation of Mendelian randomization and its use in NAFLD research.
Fig. 4: Genetic variants related to the ‘metabolically healthy obese’ phenotype.
Fig. 5: An illustration of how human genetics can guide the efforts to achieve personalized medicine.

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Acknowledgements

M.E. and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, National Health and Medical Research Council of Australia (NHMRC) Program Grants (APP1053206 and APP1149976) and Project Grants (APP1107178 and APP1108422).

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  1. Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia

    Mohammed Eslam & Jacob George

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Glossary

Metabolic syndrome

A cluster of risk factors that are associated with insulin resistance and future cardiovascular disease risk. According to the Adult Treatment Panel-III, metabolic syndrome is defined as the presence of abnormalities in at least three of the five components: elevated fasting glucose, high blood pressure, hypertriglyceridaemia, low HDL cholesterol level and elevated waist circumference.

Heritability

A statistical analysis that estimates the proportion of trait variation that is attributable to genetic variation among individuals. Heritability varies according to the studied population.

Genome-wide association study

(GWAS). An examination of a large number (hundreds of thousands) of common single-nucleotide polymorphisms across the genome of many cases and controls of a particular trait to determine whether any variant is associated with the trait.

Lipoproteins

Lipoproteins are complex particles with a core containing cholesterol esters and triglycerides surrounded by a lipid membrane; they contain proteins called apolipoproteins, which enable lipoprotein formation and function.

Lipogenesis

The metabolic process of synthesizing fatty acids from acetyl-CoA subunits for storage as fat.

Lands cycle

A metabolic remodelling pathway in the endoplasmic reticulum. The cycle is one of the major routes for acyl remodelling to modify the fatty acid composition of phospholipids.

Phenome-wide association studies

(PheWAS). An unbiased systematic approach to test for associations between a specific genetic variant or series of variants, and a wide range of phenotypes in large cohorts.

Gene effects

The estimation of the genetic determination for a particular trait using mathematical models that allows one to distinguish between environmental and genetic contributions.

HOMA-IR

Homeostatic Model Assessment of Insulin Resistance, a surrogate measure of insulin resistance.

Mendelian randomization studies

An analysis that incorporates genetic variants that are predicted to be independent of confounding factors into epidemiological studies as instrumental tools to infer causality of a risk factor or of a biomarker in a particular disease.

Phenomics

The systematic study of phenomes, a set of various phenotypes.

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Eslam, M., George, J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol 17, 40–52 (2020). https://doi.org/10.1038/s41575-019-0212-0

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