Genetic and environmental determinants of diastolic heart function
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Published version
Author(s)
Type
Journal Article
Abstract
Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on
myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes
and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac
motion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wide
association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric
function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were
independent predictors of diastolic function and we found a causal relationship between genetically-determined ventricular
stiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolic
function that are relevant for identifying causal relationships and potential tractable targets.
myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes
and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac
motion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wide
association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric
function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were
independent predictors of diastolic function and we found a causal relationship between genetically-determined ventricular
stiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolic
function that are relevant for identifying causal relationships and potential tractable targets.
Date Issued
2022-04-13
Date Acceptance
2022-03-08
Citation
Nature Cardiovascular Research, 2022, 1, pp.361-371
ISSN
2731-0590
Publisher
Nature
Start Page
361
End Page
371
Journal / Book Title
Nature Cardiovascular Research
Volume
1
Copyright Statement
This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
© The Author(s) 2022
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
© The Author(s) 2022
License URL
Sponsor
Wellcome Trust
Engineering & Physical Science Research Council (EPSRC)
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Imperial College Healthcare NHS Trust- BRC Funding
Bayer Ag
British Heart Foundation
British Heart Foundation
Engineering & Physical Science Research Council (EPSRC)
Sir Jules Thorn Charitable Trust
Identifier
https://www.nature.com/articles/s44161-022-00048-2
Grant Number
107469/Z/15/Z
EP/P001009/1
RDC04
NH/17/1/32725
RDB02
PO2150248927
RE/18/4/34215
RG/19/6/34387
EP/K030523/1
21 JTA
Publication Status
Published