title: Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
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.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Jia Nee
authors.initials: JN
authors.lastname: Foo
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.|Department of Mathematics and Statistics, Boston University, Boston, MA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: David B
authors.initials: DB
authors.lastname: Simon
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Child Study Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.|National Heart, Lung and Blood Institute, Bethesda, MD.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001794:Blood Pressure / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D015995:Prevalence; D011955:Receptors, Drug / Q000235:genetics*; D012965:Sodium Chloride / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics*
chemical_list: C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C578714:SLC12A1 protein, human; C578874:SLC12A3 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D012965:Sodium Chloride