Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_E95C7A7DDD8F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases.
Journal
Ophthalmology science
Author(s)
Tomasoni M. (co-first), Beyeler M.J. (co-first), Vela S.O. (co-first), Mounier N., Porcu E., Corre T., Krefl D., Button A.L., Abouzeid H., Konstantinidis Lazaros, Bochud M., Schlingemann R., Bergin C., Bergmann S.
ISSN
2666-9145 (Electronic)
ISSN-L
2666-9145
Publication state
Published
Issued date
09/2023
Peer-reviewed
Oui
Volume
3
Number
3
Pages
100288
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
To identify novel susceptibility loci for retinal vascular tortuosity, to better understand the molecular mechanisms modulating this trait, and reveal causal relationships with diseases and their risk factors.
Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR).
We analyzed 116 639 fundus images of suitable quality from 63 662 participants from 3 cohorts, namely the UK Biobank (n = 62 751), the Swiss Kidney Project on Genes in Hypertension (n = 397), and OphtalmoLaus (n = 512).
Using a fully automated retina image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, we computed the median arterial, venous and combined vessel tortuosity measured by the distance factor (the length of a vessel segment over its chord length), as well as by 6 alternative measures that integrate over vessel curvature. We then performed the largest GWAS of these traits to date and assessed gene set enrichment using the novel high-precision statistical method PascalX.
We evaluated the genetic association of retinal tortuosity, measured by the distance factor.
Higher retinal tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, metacohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 116 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that retinal tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, MR revealed causal effects between tortuosity, body mass index, and low-density lipoprotein.
Several alleles associated with retinal vessel tortuosity suggest a common genetic architecture of this trait with ocular diseases (glaucoma, myopia), cardiovascular diseases, and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Keywords
General Earth and Planetary Sciences, General Environmental Science, GWAS, Mendelian randomization, Microvasculature, Retina, Tortuosity
Pubmed
Web of science
Open Access
Yes
Create date
06/12/2020 23:51
Last modification date
13/10/2023 6:00
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