TY - JOUR
T1 - Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
AU - Villaplana-Velasco, Ana
AU - Pigeyre, Marie
AU - Engelmann, Justin
AU - Rawlik, Konrad
AU - Canela-Xandri, Oriol
AU - Tochel, Claire
AU - Lona-Durazo, Frida
AU - Mookiah, Muthu Rama Krishnan
AU - Doney, Alex
AU - Parra, Esteban J.
AU - Trucco, Emanuele
AU - MacGillivray, Tom
AU - Rannikmae, Kristiina
AU - Tenesa, Albert
AU - Pairo-Castineira, Erola
AU - Bernabeu, Miguel O.
N1 - Funding Information:
This research has been conducted using the UK Biobank Resource under project 788. This research was funded in part by the Medical Research Council grant (MR/N013166/1) to A.V.V. This work is supported by the Roslin Institute Strategic Programme Grant from the BBSRC (BBS/E/D/30002275 and BBS/E/D/30002276) to A.T.; Health Data Research UK grants (references HDR-9004 and HDR-9003) to A.T.; the Engineering and Physical Sciences Research Council (EPSRC) grant (EP/R029598/1, EP/T008806/1) to M.O.B.; Fondation Leducq grant (17 CVD 03) to M.O.B., the European Union’s Horizon 2020 research and innovation programme under grant agreement No 801423 to M.O.B.; Diabetes UK grant (20/0006221) to M.O.B.; Fight for Sight grant (5137/5138) to M.O.B.; and British Heart Foundation and The Alan Turing Institute (which receives core funding under the EPSRC grant EP/N510129/1) as part of the Cardiovascular Data Science Awards Round 2 (SP/19/9/34812) to M.O.B.
Copyright:
© 2023. The Author(s).
PY - 2023/5/15
Y1 - 2023/5/15
N2 - 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.
AB - 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.
KW - Humans
KW - Genome-Wide Association Study
KW - Genetic Predisposition to Disease
KW - Myocardial Infarction/genetics
KW - Coronary Artery Disease/genetics
KW - Risk Factors
UR - http://www.scopus.com/inward/record.url?scp=85159459683&partnerID=8YFLogxK
U2 - 10.1038/s42003-023-04836-9
DO - 10.1038/s42003-023-04836-9
M3 - Article
C2 - 37188768
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
M1 - 523
ER -