GWAS of Retinal Vessel Tortuosity Identifies 173 Novel Loci Revealing Genes and Pathways Associated with Vascular Pathomechanics and Cardiometabolic Diseases

Tomasoni, Mattia; Mounier, Ninon; Porcu, Eleonora; Corre, Tanguy; Abouzeid, Hana; Bochud, Murielle; Bergmann, Sven

doi:10.1101/2020.06.25.20139725

Cited by 5 publications

(10 citation statements)

References 164 publications

(374 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The direction of these estimates agrees with their phenotypical correlations and published papers 6 , suggesting a partial explanation by their common genetic basis. This finding agrees with three aforementioned studies 11,14,41 which identified novel retinal width and tortuosity loci associated with CAD but did not estimate a genetic correlation between retinal phenotypes and CAD. In summary, our analysis characterises the genetic architecture of D f and highlights a common genetic basis with cardiovascular diseases, which partly explains the inverse association between D f and coronary vessels dysfunction.…”

Section: Discussionsupporting

confidence: 92%

“…The SNP heritability (h 2 SNP) of the left and right Df estimate are respectively 0.09 (0.015) and 0.10 (0.014). These h 2 SNP magnitude is in line with previous results from retinal vascular tortuosity 11,14 , retinal width 12 , and the recently published Df 26 GWAS.…”

Section: Gwas Reveals Nine Fractal Dimension Loci and Their Association With Cardiovascular Risk Factorssupporting

confidence: 91%

“…We discovered 9 loci associated with Df with similar effect across European, Asian, and African UKBB participants. Most of these genetic variants are relevant to multiple traits and diseases; for instance, the one located near HERC2 has been previously associated with hair 34 , skin 35 , and eye colour 36 ; but recent studies also suggest a strong effect in AMD 37 , glaucoma 38 , intraocular pressure 39 , visual acuity 40 , retinal arterial width 41 and arterial and venular retinal tortuosity 11,14 . Another interesting associated SNP is the one near the SLC12A9 gene as it has been reported in pigmentation [34][35][36] , mean arterial pressure 42 , and resting heart rate 43 GWAS.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence points towards coronary and retinal vessels experiencing similar pathophysiological changes at even early CAD stages [6][7][8] , plausibly influenced by a shared genetic basis 7,[9][10][11][12][13][14] . Population-based studies have demonstrated that both tortuosity and width of arteries and veins have a moderate genetic basis 12,13 .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Velasco

Engelmann

Rawlik

et al. 2021

Preprint

View full text Add to dashboard Cite

There is increasing evidence that the complexity of the retinal vasculature (measured as fractal dimension, Df) might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present here a genome-wide association study (GWAS) aimed to elucidate the genetic component of Df and to analyse its relationship with CAD. To this end, we obtained Df from retinal fundus images and genotyping information from ∼38,000 white-British participants in the UK Biobank. We discovered 9 loci associated with Df, previously reported in pigmentation, retinal width and tortuosity, hypertension, and CAD studies. Significant negative genetic correlation estimates endorse the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD fatal outcomes. This strong association motivated us to developing a MI predictive model combining clinical information, Df, a CAD polygenic risk score and using a random forest algorithm. Internal cross validation evidenced a considerable improvement in the area under the curve (AUC) of our predictive model (AUC=0.770) when comparing with an established risk model, SCORE, (AUC=0.719). Our findings shed new light on the genetic basis of Df, unveiling a common control with CAD, and highlights the benefits of its application in individualised MI risk prediction.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Gwas Reveals Nine Fractal Dimension Loci and Their Association With Cardiovascular Risk Factorssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Velasco

Engelmann

Rawlik

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…76 It was also suggestively associated with vascular FD (β, −0.069 SD; P =1.06×10 − 7 ). Further sensitivity analyses and comparison with variants identified in a previous GWAS of vascular tortuosity 24 are provided in the Supplemental Results (Figure S13 and S14 and Table S12).…”

Section: Resultsmentioning

confidence: 99%

Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature

et al. 2022

View full text Add to dashboard Cite

Background: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health as well as tumorigenesis. The retinal fundus is a window for human in vivo non-invasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. Methods: We utilized 97,895 retinal fundus images from 54,813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated fractal dimension (FD) as a measure of vascular branching complexity, and vascular density. We associated these indices with 1,866 incident ICD-based conditions (median 10y follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Results: Low retinal vascular FD and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular FD and density identified 7 and 13 novel loci respectively, which were enriched for pathways linked to angiogenesis (e.g., VEGF, PDGFR, angiopoietin, and WNT signaling pathways) and inflammation (e.g., interleukin, cytokine signaling). Conclusions: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights on genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health records, biomarker, and genetic data to inform risk prediction and risk modification.

show abstract

Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes

et al. 2023

View full text Add to dashboard Cite

There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, Df, might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of Df and analyse its relationship with CAD. We replicated 5 Df loci and found 4 additional loci with suggestive significance (P < 1e−05) to contribute to Df variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD’s fatal outcomes. Fine-mapping of Df loci revealed Notch signalling regulatory variants supporting a shared mechanism with MI outcomes. We developed a predictive model for MI incident cases, recorded over a 10-year period following clinical and ophthalmic evaluation, combining clinical information, Df, and a CAD polygenic risk score. Internal cross-validation demonstrated a considerable improvement in the area under the curve (AUC) of our predictive model (AUC = 0.770 ± 0.001) when comparing with an established risk model, SCORE, (AUC = 0.741 ± 0.002) and extensions thereof leveraging the PRS (AUC = 0.728 ± 0.001). This evidences that Df provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of Df, unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.

show abstract

GWAS of Retinal Vessel Tortuosity Identifies 173 Novel Loci Revealing Genes and Pathways Associated with Vascular Pathomechanics and Cardiometabolic Diseases

Cited by 5 publications

References 164 publications

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control

Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature

Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes

Contact Info

Product

Resources

About