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Rare independent mutations in renal salt handling genes contribute to blood pressure variation

Nature Genetics volume 40, pages 592–599 (2008)Cite this article

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Abstract

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes—SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)—causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

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Figure 1: Proven and inferred mutations in SLC12A3, SLC12A1 and KCNJ1 in the Framingham Heart Study offspring cohort.
Figure 2: Heterozygous mutations in SLC12A3, SLC12A1 and KCNJ1 lower blood pressure.
Figure 3: Correlation of blood pressures among sibling pairs in Framingham Heart Study.
Figure 4: Reduced prevalence of hypertension among mutation carriers.

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Change history

  • 13 April 2008

    In the version of this article initially published online, an equal contribution statement was missing for the first two authors Weizhen Ji and Jia Nee Foo. These authors should be identified as equal contributors to the manuscript. The error has been corrected for all versions of the article

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Acknowledgements

We thank C. Nelson-Williams for management of the DNA database. J.N.F. is supported by the Agency for Science, Technology and Research, Singapore. This work was supported in part by a US National Institutes of Health Specialized Center of Research in Hypertension grant (to R.P.L.) and the US National Heart, Lung and Blood Institute's Framingham Heart Study contract NO1-HC-25195.

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Author notes

  1. Weizhen Ji and Jia Nee Foo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, 06510, Connecticut, USA

    Weizhen Ji, Jia Nee Foo, Brian J O'Roak, Hongyu Zhao, David B Simon, Matthew W State & Richard P Lifton

  2. Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, 06510, Connecticut, USA

    Weizhen Ji, Jia Nee Foo, David B Simon & Richard P Lifton

  3. Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, 06510, Connecticut, USA

    Hongyu Zhao

  4. National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, 01702, Massachusetts, USA

    Martin G Larson, Christopher Newton-Cheh & Daniel Levy

  5. Department of Mathematics and Statistics, Boston University, 111 Cummington Street, Boston, 02215, Massachusetts, USA

    Martin G Larson

  6. Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, 06520, Connecticut, USA

    Matthew W State

  7. National Heart, Lung and Blood Institute, 31 Center Drive, Bethesda, 20892, Maryland, USA

    Daniel Levy

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Correspondence to Richard P Lifton.

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Ji, W., Foo, J., O'Roak, B. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40, 592–599 (2008). https://doi.org/10.1038/ng.118

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