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, 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.
AB - 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.
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 -