Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Date Issued
2022-08-03
Date Acceptance
2022-07-20
Citation
Nature Communications, 2022, 13
ISSN
2041-1723
Publisher
Nature Research
Journal / Book Title
Nature Communications
Volume
13
Copyright Statement
© The Author(s) 2022. 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/.
License URL
Sponsor
UK DRI Ltd
Grant Number
World Class Labs 2 scheme
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SMALL-VESSEL DISEASE
PULSE-WAVE VELOCITY
LOEYS-DIETZ SYNDROME
MENDELIAN RANDOMIZATION
ARTERIAL STIFFNESS
CARDIOVASCULAR-DISEASE
MISSENSE MUTATION
GENETIC-VARIANTS
RISK
METAANALYSIS
Aorta
Aortic Aneurysm
Female
Genome-Wide Association Study
Humans
Male
Phenomics
White Matter
Aorta
Humans
Aortic Aneurysm
Female
Male
Genome-Wide Association Study
White Matter
Phenomics
Publication Status
Published
Article Number
ARTN 4505