Discovery of rare variants associated with blood pressure regulation trhough meta-analaysis of 1.3 million individuals
File(s)Surendran P et al Nat Genet accepted manuscript.pdf (1.57 MB)
Accepted version
Author(s)
Type
Journal Article
Abstract
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs 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 (e.g.GATA5, 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.
Date Issued
2020-12
Date Acceptance
2020-09-08
Citation
Nature Genetics, 2020, 52, pp.1314-1332
ISSN
1061-4036
Publisher
Nature Research
Start Page
1314
End Page
1332
Journal / Book Title
Nature Genetics
Volume
52
Copyright Statement
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2020. The final publication is available at Springer via https://doi.org/10.1038/s41588-020-00713-x
Sponsor
Home Office
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
UNIVERSITY OF OULU
Identifier
https://www.nature.com/articles/s41588-020-00713-x
Grant Number
PG0484
RDF03
MR/L01341X/1
Nil
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
COMMON VARIANTS
IDENTIFIES COMMON
LOCI
RISK
FREQUENCY
TRAITS
HYPERTENSION
GENETICS
Blood Pressure
GATA5 Transcription Factor
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Hypertension
Mutation
Phospholipase C beta
Polymorphism, Single Nucleotide
LifeLines Cohort Study
EPIC-CVD
EPIC-InterAct
Understanding Society Scientific Group
Million Veteran Program
Humans
Hypertension
Genetic Predisposition to Disease
Blood Pressure
Gene Frequency
Genotype
Mutation
Polymorphism, Single Nucleotide
GATA5 Transcription Factor
Phospholipase C beta
Genome-Wide Association Study
06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status
Published
Date Publish Online
2020-11-23