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

Mattia Tomasoni, PhD; Michael Johannes Beyeler, MSc; Sofia Ortin Vela, MSc; Ninon Mounier, PhD; Eleonora Porcu, PhD; Tanguy Corre, PhD; Daniel Krefl, PhD; Alexander Luke Button, PhD; Hana Abouzeid, MD; Konstantinidis Lazaros, MD; Murielle Bochud, MD, PhD; Reinier Schlingemann, MD, PhD; Ciara Bergin, PhD; Sven Bergmann, PhD

Ophthalmology Science (Sep 2023)

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

Mattia Tomasoni, PhD,
Michael Johannes Beyeler, MSc,
Sofia Ortin Vela, MSc,
Ninon Mounier, PhD,
Eleonora Porcu, PhD,
Tanguy Corre, PhD,
Daniel Krefl, PhD,
Alexander Luke Button, PhD,
Hana Abouzeid, MD,
Konstantinidis Lazaros, MD,
Murielle Bochud, MD, PhD,
Reinier Schlingemann, MD, PhD,
Ciara Bergin, PhD,
Sven Bergmann, PhD

Affiliations

Mattia Tomasoni, PhD: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Jules-Gonin Eye Hospital, Lausanne, Switzerland
Michael Johannes Beyeler, MSc: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Sofia Ortin Vela, MSc: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Ninon Mounier, PhD: Swiss Institute of Bioinformatics, Lausanne, Switzerland; Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
Eleonora Porcu, PhD: Swiss Institute of Bioinformatics, Lausanne, Switzerland; Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Tanguy Corre, PhD: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
Daniel Krefl, PhD: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Alexander Luke Button, PhD: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Hana Abouzeid, MD: Division of Ophthalmology, Geneva University Hospitals, Geneva, Switzerland; Clinical Eye Research Center Memorial Adolphe de Rothschild, Geneva, Switzerland
Konstantinidis Lazaros, MD: Jules-Gonin Eye Hospital, Lausanne, Switzerland
Murielle Bochud, MD, PhD: Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
Reinier Schlingemann, MD, PhD: Jules-Gonin Eye Hospital, Lausanne, Switzerland
Ciara Bergin, PhD: Jules-Gonin Eye Hospital, Lausanne, Switzerland
Sven Bergmann, PhD: Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa; Correspondence: Sven Bergmann, PhD, University of Lausanne, Genopode, Lausanne 1016, Switzerland.

Journal volume & issue: Vol. 3, no. 3
p. 100288

Abstract

Read online

Purpose: 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. Design: Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR). Participants: 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). Methods: 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. Main Outcome Measure: We evaluated the genetic association of retinal tortuosity, measured by the distance factor. Results: 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. Conclusions: 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. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Published in Ophthalmology Science

ISSN: 2666-9145 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Ophthalmology
Website: https://www.journals.elsevier.com/ophthalmology-science/

About the journal

Abstract

Keywords