GWAS of Retinal Vessel Tortuosity Identifies 173 Novel Loci Revealing Genes and Pathways Associated with Vascular Pathomechanics and Cardiometabolic Diseases
Authors: Tomasoni Mattia , Beyeler Michael Johannes , Vela Sofia Ortin , Mounier Ninon , Porcu Eleonora , Corre Tanguy , Krefl Daniel , Button Alexander Luke , Abouzeid Hana , Lazaros Konstantinidis , Bochud Murielle , Schlingemann Reinier , Bergin Ciara , Bergmann Sven 
Published: June 2020

AbstractBackgroundFundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Blood vessel tortuosity is a morphological feature associated with many diseases including hypertension.MethodsWe analyzed 116 639 fundus images of suitable quality from 63 662 participants from three cohorts, namely the UK Biobank (n = 62 751), SKIPOGH (n = 397), andOphtalmoLaus(n = 512). We used a fully automated image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, characterizing these subjects in terms of their median retinal vessel tortuosity specific to arteries and to veins. Tortuosity was measured by thedistance factor(the length of a vessel segment over its chord length), as well as measures that integrate over vessel curvature. Using these measures as traits, we performed the largest genome-wide association study (GWAS) of vessel tortuosity to date. We assessed gene set enrichment using the novel high-precision statistical methodPascalX.ResultsHigher 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, meta-cohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 114 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 tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, Mendelian randomization revealed causal effects between tortuosity, BMI and LDL.ConclusionsSeveral alleles associated with retinal vessel tortuosity point to a common genetic architecture of this trait with 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.Clinical PerspectiveWhat is new?We automatically estimated arterial and venous tortuosity in over 100k retinal fundus images using image analysis and deep learning.GWAS revealed 173 novel loci.Mendelian randomization showed that increased venous tortuosity reduces BMI whereas elevated LDL levels reduce the tortuosity of both arteries and veins.Measuring tortuosity in terms of thedistance factor, which is sensitive to total vessel elongation, had higher heritability and more associated loci than other tortuosity measures that are sensitive to local vessel bending.What are the clinical implications?Tortuosity genes were overexpressed in the aorta, tibial artery, coronary artery, and in two heart tissues.Higher tortuosity was associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis and hypertension.We demonstrated a shared genetic architecture between retinal tortuosity and certain diseases related to the vasculature, and the associations included several cardiometabolic disease variants and risk factors. Further research is needed to investigate the potential of the retinal vessel tortuosity as a clinically relevant biomarker for cardiovascular disease and metabolic syndrome.Enriched pathways include a well-known therapeutic target for ocular diseases (VEGFA-VEGFR2) affecting tissue remodeling. We highlight several transcription factors as interesting targets for further experimentation.