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The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus

Nature Reviews Nephrology volume 7, pages 313–326 (2011)Cite this article

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Abstract

Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research.

Key Points

  • Population genetic studies have identified loci that confer susceptibility to many common forms of kidney disease; however, ascertaining the underlying biologic mechanisms is often a challenge

  • Linkage disequilibrium, admixture and genetic variation are some of the key factors underlying the success of population-based approaches to the discovery of genes that are associated with disease

  • Population genetics research identified a region on chromosome 22q12 containing DNA sequence variants associated with a predisposition to many diabetes-unrelated forms of kidney disease in African and Hispanic Americans

  • The MYH9 gene was initially thought to harbor these mutations, but the neighboring gene APOL1 was subsequently identified as being more strongly associated with kidney disease

  • APOL1 mutations confer protection against sleeping sickness, which might explain the high prevalence of kidney disease in persons whose ancestry links them to geographic regions with past trypanosomal exposure

  • APOL1 genotyping has potential clinical applications for management of hypertension in individuals with kidney disease, management of patients with HIV-associated nephropathy, and for donors and recipients in kidney transplantation

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Figure 1: The effect of recombination on linkage disequilibrium and haplotype blocks.
Figure 2: Discovering associations with a disease through admixture mapping.
Figure 3: Chromosomal region associated with diabetes-unrelated ESRD phenotypes in African Americans.
Figure 4: Contour maps of allele frequency distributions of identified APOL1 risk variants in a number of African countries.
Figure 5: Presumed order of occurrence of MYH9 and APOL1 variants in human evolutionary history.
Figure 6: Positive selection pressure and selective sweeps.

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Acknowledgements

K. Skorecki acknowledges the support of the Canadian and American Technion Societies (Eshagian Estate Fund, Dr Sidney Kremer Kidney Disease Research Fund), the Israel Science Foundation (grant number 890015), and the Legacy Heritage Fund. S. Rosset acknowledges the support of European Research Commission grant MIRG-CT-2007-208019, Israel Science Foundation (grant number 1227/09) and an IBM Open Collaborative Research grant. D. M. Behar thanks the European Commission, Directorate-General for Research for FP7 Ecogene grant 205419.

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Authors and Affiliations

  1. Department of Statistics and Operations Research, Tel Aviv University, 69978, Tel Aviv, Israel

    Saharon Rosset

  2. Ruth and Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 31096, Haifa, Israel

    Shay Tzur & Karl Skorecki

  3. Molecular Medicine Laboratory, Rambam Health Care Campus, 31096, Haifa, Israel

    Doron M. Behar

  4. Hadassah Medical Center, 91120, Jerusalem, Israel

    Walter G. Wasser

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  1. Saharon Rosset
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  2. Shay Tzur
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Contributions

S. Rosset, S. Tzur, W. G. Wasser and K. Skorecki contributed equally to all aspects of the manuscript. D. Behar made a substantial contribution to discussion of content and review and/or editing of the manuscript before submission.

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Correspondence to Karl Skorecki.

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Supplementary information

Supplementary Figure 1

Modeled structure of the SRA interacting domain of the C-terminus of the APOL1 gene product. (TIFF 225 kb)

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Rosset, S., Tzur, S., Behar, D. et al. The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus. Nat Rev Nephrol 7, 313–326 (2011). https://doi.org/10.1038/nrneph.2011.52

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