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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-04-06

AUTHORS

Weizhen Ji, Jia Nee Foo, Brian J O'Roak, Hongyu Zhao, Martin G Larson, David B Simon, Christopher Newton-Cheh, Matthew W State, Daniel Levy, Richard P Lifton

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. More... »

PAGES

592-599

Journal

TITLE

Nature Genetics

ISSUE

5

VOLUME

40

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.118

DOI

http://dx.doi.org/10.1038/ng.118

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1049828769

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18391953


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38 schema:description 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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45 Heart Study
46 KCNJ1
47 SLC12A1
48 alleles
49 architecture
50 benefits
51 biochemistry
52 blood pressure
53 blood pressure reduction
54 blood pressure variation
55 common complex diseases
56 common complex traits
57 common variants
58 comparative genomics
59 complex diseases
60 complex traits
61 development
62 development of hypertension
63 disease
64 effect
65 effects of alleles
66 findings
67 general population
68 genes
69 genetic architecture
70 genetics
71 genomics
72 health benefits
73 hypertension
74 implications
75 independent mutations
76 large reduction
77 loci
78 members
79 mutations
80 number
81 population
82 pressure
83 pressure reduction
84 pressure variation
85 rare alleles
86 rare recessive disease
87 recessive disease
88 reduction
89 renal salt
90 risk alleles
91 salt
92 selection
93 significant blood pressure reduction
94 small number
95 study
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