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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Surendran, Praveen ; Fava, Cristiano LU ; Melander, Olle LU orcid ; Orho-Melander, Marju LU ; Poveda, Alaitz LU orcid ; V. Varga, Tibor LU ; Renström, Frida LU ; Franks, Paul LU ; Tuomi, Tiinamaija LU orcid and Almgren, Peter LU , et al. (2020) In Nature Genetics 52(12). p.1314-1332
Abstract
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin... (More)
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. (Less)
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author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Genetics
volume
52
issue
12
pages
19 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85096546970
  • pmid:33230300
ISSN
1546-1718
DOI
10.1038/s41588-020-00713-x
language
English
LU publication?
yes
additional info
Export Date: 9 December 2020
id
ab3cf679-db71-435f-9907-67f295345e04
date added to LUP
2020-12-09 11:06:18
date last changed
2024-05-02 21:28:43
@article{ab3cf679-db71-435f-9907-67f295345e04,
  abstract     = {{Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency &gt; 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P &lt; 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.}},
  author       = {{Surendran, Praveen and Fava, Cristiano and Melander, Olle and Orho-Melander, Marju and Poveda, Alaitz and V. Varga, Tibor and Renström, Frida and Franks, Paul and Tuomi, Tiinamaija and Almgren, Peter and Groop, Leif and Howson, Joanna M. M.}},
  issn         = {{1546-1718}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1314--1332}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals}},
  url          = {{http://dx.doi.org/10.1038/s41588-020-00713-x}},
  doi          = {{10.1038/s41588-020-00713-x}},
  volume       = {{52}},
  year         = {{2020}},
}