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

Ana Villaplana-Velasco, Marie Pigeyre, Justin Engelmann, Konrad Rawlik, Oriol Canela-Xandri, Claire Tochel, Frida Lona-Durazo, Muthu Rama Krishnan Mookiah, Alex Doney, Esteban J. Parra, Emanuele Trucco, Tom MacGillivray, Kristiina Rannikmae, Albert Tenesa, Erola Pairo-Castineira, Miguel O. Bernabeu (Lead / Corresponding author)

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2 Citations (Scopus)
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There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, D f, 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 D f 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 D f and analyse its relationship with CAD. We replicated 5 D f loci and found 4 additional loci with suggestive significance (P < 1e−05) to contribute to D f variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between D f and CAD, and between D f and myocardial infarction (MI), one of CAD’s fatal outcomes. Fine-mapping of D f 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, D f, 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 D f provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of D f, unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.

Original languageEnglish
Article number523
Number of pages13
JournalCommunications Biology
Publication statusPublished - 15 May 2023


  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Myocardial Infarction/genetics
  • Coronary Artery Disease/genetics
  • Risk Factors

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences
  • General Biochemistry,Genetics and Molecular Biology
  • Medicine (miscellaneous)


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