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.Correspondence to: Richard Lifton richard.lifton@yale.edu 203-737-4420 Howard Hughes Medical Institute, Yale University School of Medicine, TAC Room S341D, 1 Gilbert Street, New Haven, CT 06510, USA. Accession Numbers. GenBank mRNA sequences are as follows: NCCT/SLC12A3 (NM_000339); NKCC2/SLC12A1 (NM_000338); ROMK/KCNJ1 (NM_000220, NM_153764-7). GenBank protein sequences are as follows: SLC12A3 orthologs: Human (NP_000330), mouse (NP_062288), rat (NP_062218), rabbit (AAC33139), dog (XP_535292), cow (XP_871112), chicken (XP_414059), zebrafish (NP_001038545) and winter flounder (AAL26926); SLC12A1orthologs: Human (NP_000329), mouse (NP_899197), rat (NP_062007), rabbit (AAB03494), dog (XP_850426), chicken (XP_413814), zebrafish (NP_001002080) and Tetraodon (CAF99849); SLC12A1-3 invertebrate orthologs: S. purpuratus (XP_783014), C. elegans (NP_502704) and D. melanogaster (NP_648572); KCNJ1 orthologs: Human (NP_72245), mouse (NP_062633), rat (NP_058719), dog (XP_546403), chicken (XP_425795), cow (XP_585917), frog (AAH79788), zebrafish (XP_684541), fugu (ABB87033), C.elegans (NP_509138), S. purpuratus (XP_789112) and D. melanogaster (NP_651131); Other human paralogs: SLC12A2 (NP_001037), SLC12A4 (NP_005063), SLC12A5 (NP_065759), SLC12A6 (NP_005126) and SLC12A7 (NP_006589), KCNJ2 (NP_000882), KCNJ3 (NP_002230) KCNJ4 (NP_004972), KCNJ5 (NP_000881), KCNJ6 (NP_002231), KCNJ8 (NP_004973), KCNJ9 (NP_004974), KCNJ10 (NP_002232), KCNJ11 (NP_000516), KCNJ12 (NP_066292), KCNJ13 (NP_002233), KCNJ14 (NP_733838), KCNJ15 (NP_733933) and KCNJ16 (NP_733938).
NIH Public AccessAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2013 September 08.
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NIH-PA Author ManuscriptHypertension affects 1 billion people world-wide and is a major contributor to death from stroke, myocardial infarction, end-stage renal disease and congestive heart failure. Although epidemiologic studies have demonstrated high heritability of blood pressure...