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Genome-wide association studies and genetic risk assessment of liver diseases

Nature Reviews Gastroenterology & Hepatology volume 7, pages 669–681 (2010)Cite this article

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Abstract

Genetic tests can help clinicians to diagnose rare monogenic liver diseases. For most common liver diseases, however, multiple gene variants that have small to moderate individual phenotypic effects contribute to the overall risk of disease. An individual's level of risk depends on interactions between environmental factors and a wide range of modifier genes, which are yet to be identified systematically. The latest genome-wide association studies in large cohorts of patients with gallstones, fatty liver disease, viral hepatitis, chronic cholestatic liver diseases or drug-induced liver injury have provided new insights into the pathophysiology of these illnesses and have suggested the contribution of previously unsuspected pathogenic pathways. Studies in mouse models have identified further susceptibility genes for several complex liver diseases. As a result, in the future polygenic risk scores might help to define subgroups of patients at risk of developing liver diseases who would benefit from preventative measures and/or personalized therapy. Now that whole-genome sequencing is possible, comprehensive strategies for integrating genomic data and counseling of patients need to be developed.

Key Points

  • Many so-called simple genetic tests do not provide a clear-cut diagnosis of monogenic liver diseases

  • Future risk assessments for complex, multifactorial, liver diseases might be based on polygenic risk scores (derived from genome-wide association studies) that illustrate disease predisposition

  • Risk information based on genome-wide association studies will be difficult to communicate to patients, but its individualized nature might help motivate patients to make lifestyle modifications

  • Polygenic risk scores will require rigorous prospective evaluation before they are used in clinical practice

  • Hepatologists need to develop concepts for personalized prevention and therapy that integrate genetic risk assessment (and, perhaps, the results of direct-to-consumer genetic tests)

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Figure 1: Most common liver diseases are complex (multifactorial), which means that they are determined by multiple genetic factors and their interactions (also termed epistasis).
Figure 2: Genetic risk factors for liver diseases.
Figure 3: Schematic Manhattan plot presenting the results of a hypothetical genome-wide association study.

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Acknowledgements

This Review extends the concepts presented by F. Lammert in an invited lecture, “Assessment of genetic risk in liver disease”, which formed part of the postgraduate course The changing face of hepatology—integrating scientific concepts into patient care of the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), San Francisco, CA, USA, October 2008.

Experimental work related to the topic is supported by Deutsche Forschungsgemeinschaft (SFB/TRR 57), Helmholtz Association (German Network for Systems Genetics GENESYS) and EU (COST Action BM0901 SYSGENET).

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  1. Department of Medicine II, Saarland University Hospital, Saarland University, 66421, Homburg, Germany

    Marcin Krawczyk, Roman Müllenbach, Susanne N. Weber, Vincent Zimmer & Frank Lammert

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  1. Marcin Krawczyk
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  2. Roman Müllenbach
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  3. Susanne N. Weber
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  4. Vincent Zimmer
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Contributions

M. Krawczyk contributed to researching data for the article, writing and reviewing and editing the manuscript before submission. R. Müllenbach contributed to discussion of the content, writing and reviewing and editing the manuscript before submission. S. N. Weber contributed to researching data for the article and writing the article. V. Zimmer contributed to researching data for the article and to discussion of the content. F. Lammert contributed to researching data for the article, writing and reviewing and editing the manuscript before submission.

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Correspondence to Frank Lammert.

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Krawczyk, M., Müllenbach, R., Weber, S. et al. Genome-wide association studies and genetic risk assessment of liver diseases. Nat Rev Gastroenterol Hepatol 7, 669–681 (2010). https://doi.org/10.1038/nrgastro.2010.170

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