Article abstract
Nature Genetics 40, 592 - 599 (2008)
Published online: 6 April 2008 | Corrected online: 13 April 2008 | doi:10.1038/ng.118
Rare independent mutations in renal salt handling genes contribute to blood pressure variation
Weizhen Ji1,2,8, Jia Nee Foo1,2,8, Brian J O'Roak1, Hongyu Zhao1,3, Martin G Larson4,5, David B Simon1,2, Christopher Newton-Cheh4, Matthew W State1,6, Daniel Levy4,7 & Richard P Lifton1,2
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.
- Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
- Howard Hughes Medical Institute, Yale University School of Medicine, 295 Congress Avenue, New Haven, Connecticut 06510, USA.
- Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, Connecticut 06510, USA.
- National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702, USA.
- Department of Mathematics and Statistics, Boston University, 111 Cummington Street, Boston, Massachusetts 02215, USA.
- Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, Connecticut 06520, USA.
- National Heart, Lung and Blood Institute, 31 Center Drive, Bethesda, Maryland 20892, USA.
- These authors contributed equally to this work.
Correspondence to: Richard P Lifton1,2 e-mail: richard.lifton@yale.edu
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