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

Abstract

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.

Proteome-wide Mendelian randomization study implicates inflammaging biomarkers in retinal vasculature, cardiometabolic diseases and longevity

“…Finally, reverse MR suggested that circulating FOXO3 levels may be a blood biomarker for changes in retinal vascular D f . The findings from the D f GWAS meta-analysis were consistent with previous genetic analyses on retinal D f , thus, supporting the biologically coherent relationships of D fassociated variants with various ocular and cardiovascular traits and diseases 5,10,35 . Interestingly, we found that several loci were also associated with either cardiovascular risk factors (e.g., hypertension, and dyslipidaemia) or diseases (e.g., coronary artery diseases), as well as inflammatory and immune responses 20,21,22,23,24,25,26,27,28 .…”

“…We found nominally significant negative correlations of D f with C-reactive protein (r g = -0.13 ± 0.05), atherosclerosis (r g = -0.24 ± 0.03), coronary artery disease (r g = -0.12 ± 0.06), stroke (r g = -0.23 ± 0.09), and a positive correlation with longevity (r g = 0.12 ± 0.06) (Suppl Table 6). Such findings were consistent with the findings that we previously reported for analysis conducted in a subset of UKBB individuals 10 .…”

“…To the best of our knowledge, this study is the largest GWAS meta-analysis for retinal D f to date. We identified eight novel loci associated with D f , and replicated the associations of four previously identified variants 5,10 . We also confirmed genetic correlations between D f and systemic inflammation, cardiovascular disease, stroke and longevity, and identified circulating MMP12 and IgG Fc recIIb levels as key mediators linking D f to cardiometabolic and longevity outcomes.…”

“…Previous studies focused on the links between D f and diseases, and showed that a lower D f was associated with a higher risk of mortality, incident hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, and was causally associated with skin cancer and retinal detachment 5,10 . However, none of those studies investigated the molecular mechanisms linking D f to such diseases.…”

Is Attention all You Need in Medical Image Analysis? A Review

“…They showed that their technique can work as a generalized approach for retinal morphology analyses. Of note, such hybrid models can be impactful, since retinal imaging is not only used to assess ophthalmic pathologies, but also changes in retinal morphologies that may occur early in a broad spectrum of diseases, such as Alzheimer's [154], cardiac pathologies [155], cerebral small vessel disease [156] and others. Wang et al have proposed the MsTGANet, a UNet model enhanced with a Transformer block that consists of a series of multi-head self-attention mechanisms incorporated in the encoder, to capture both local and global pixel interactions early in the learning process [45].…”