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 co...
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Autor*in:	Ana Villaplana-Velasco [verfasserIn] Marie Pigeyre [verfasserIn] Justin Engelmann [verfasserIn] Konrad Rawlik [verfasserIn] Oriol Canela-Xandri [verfasserIn] Claire Tochel [verfasserIn] Frida Lona-Durazo [verfasserIn] Muthu Rama Krishnan Mookiah [verfasserIn] Alex Doney [verfasserIn] Esteban J. Parra [verfasserIn] Emanuele Trucco [verfasserIn] Tom MacGillivray [verfasserIn] Kristiina Rannikmae [verfasserIn] Albert Tenesa [verfasserIn] Erola Pairo-Castineira [verfasserIn] Miguel O. Bernabeu [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Übergeordnetes Werk:	In: Communications Biology - Nature Portfolio, 2018, 6(2023), 1, Seite 13
Übergeordnetes Werk:	volume:6 ; year:2023 ; number:1 ; pages:13

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s42003-023-04836-9

Katalog-ID:	DOAJ090525108

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allfields	10.1038/s42003-023-04836-9 doi (DE-627)DOAJ090525108 (DE-599)DOAJ9575d863a72646d1847fcdfd16c30071 DE-627 ger DE-627 rakwb eng QH301-705.5 Ana Villaplana-Velasco verfasserin aut Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Biology (General) Marie Pigeyre verfasserin aut Justin Engelmann verfasserin aut Konrad Rawlik verfasserin aut Oriol Canela-Xandri verfasserin aut Claire Tochel verfasserin aut Frida Lona-Durazo verfasserin aut Muthu Rama Krishnan Mookiah verfasserin aut Alex Doney verfasserin aut Esteban J. Parra verfasserin aut Emanuele Trucco verfasserin aut Tom MacGillivray verfasserin aut Kristiina Rannikmae verfasserin aut Albert Tenesa verfasserin aut Erola Pairo-Castineira verfasserin aut Miguel O. Bernabeu verfasserin aut In Communications Biology Nature Portfolio, 2018 6(2023), 1, Seite 13 (DE-627)101369080X 23993642 nnns volume:6 year:2023 number:1 pages:13 https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 kostenfrei https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/toc/2399-3642 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2023 1 13
spelling	10.1038/s42003-023-04836-9 doi (DE-627)DOAJ090525108 (DE-599)DOAJ9575d863a72646d1847fcdfd16c30071 DE-627 ger DE-627 rakwb eng QH301-705.5 Ana Villaplana-Velasco verfasserin aut Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Biology (General) Marie Pigeyre verfasserin aut Justin Engelmann verfasserin aut Konrad Rawlik verfasserin aut Oriol Canela-Xandri verfasserin aut Claire Tochel verfasserin aut Frida Lona-Durazo verfasserin aut Muthu Rama Krishnan Mookiah verfasserin aut Alex Doney verfasserin aut Esteban J. Parra verfasserin aut Emanuele Trucco verfasserin aut Tom MacGillivray verfasserin aut Kristiina Rannikmae verfasserin aut Albert Tenesa verfasserin aut Erola Pairo-Castineira verfasserin aut Miguel O. Bernabeu verfasserin aut In Communications Biology Nature Portfolio, 2018 6(2023), 1, Seite 13 (DE-627)101369080X 23993642 nnns volume:6 year:2023 number:1 pages:13 https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 kostenfrei https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/toc/2399-3642 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2023 1 13
allfields_unstemmed	10.1038/s42003-023-04836-9 doi (DE-627)DOAJ090525108 (DE-599)DOAJ9575d863a72646d1847fcdfd16c30071 DE-627 ger DE-627 rakwb eng QH301-705.5 Ana Villaplana-Velasco verfasserin aut Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Biology (General) Marie Pigeyre verfasserin aut Justin Engelmann verfasserin aut Konrad Rawlik verfasserin aut Oriol Canela-Xandri verfasserin aut Claire Tochel verfasserin aut Frida Lona-Durazo verfasserin aut Muthu Rama Krishnan Mookiah verfasserin aut Alex Doney verfasserin aut Esteban J. Parra verfasserin aut Emanuele Trucco verfasserin aut Tom MacGillivray verfasserin aut Kristiina Rannikmae verfasserin aut Albert Tenesa verfasserin aut Erola Pairo-Castineira verfasserin aut Miguel O. Bernabeu verfasserin aut In Communications Biology Nature Portfolio, 2018 6(2023), 1, Seite 13 (DE-627)101369080X 23993642 nnns volume:6 year:2023 number:1 pages:13 https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 kostenfrei https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/toc/2399-3642 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2023 1 13
allfieldsGer	10.1038/s42003-023-04836-9 doi (DE-627)DOAJ090525108 (DE-599)DOAJ9575d863a72646d1847fcdfd16c30071 DE-627 ger DE-627 rakwb eng QH301-705.5 Ana Villaplana-Velasco verfasserin aut Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Biology (General) Marie Pigeyre verfasserin aut Justin Engelmann verfasserin aut Konrad Rawlik verfasserin aut Oriol Canela-Xandri verfasserin aut Claire Tochel verfasserin aut Frida Lona-Durazo verfasserin aut Muthu Rama Krishnan Mookiah verfasserin aut Alex Doney verfasserin aut Esteban J. Parra verfasserin aut Emanuele Trucco verfasserin aut Tom MacGillivray verfasserin aut Kristiina Rannikmae verfasserin aut Albert Tenesa verfasserin aut Erola Pairo-Castineira verfasserin aut Miguel O. Bernabeu verfasserin aut In Communications Biology Nature Portfolio, 2018 6(2023), 1, Seite 13 (DE-627)101369080X 23993642 nnns volume:6 year:2023 number:1 pages:13 https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 kostenfrei https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/toc/2399-3642 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2023 1 13
allfieldsSound	10.1038/s42003-023-04836-9 doi (DE-627)DOAJ090525108 (DE-599)DOAJ9575d863a72646d1847fcdfd16c30071 DE-627 ger DE-627 rakwb eng QH301-705.5 Ana Villaplana-Velasco verfasserin aut Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Biology (General) Marie Pigeyre verfasserin aut Justin Engelmann verfasserin aut Konrad Rawlik verfasserin aut Oriol Canela-Xandri verfasserin aut Claire Tochel verfasserin aut Frida Lona-Durazo verfasserin aut Muthu Rama Krishnan Mookiah verfasserin aut Alex Doney verfasserin aut Esteban J. Parra verfasserin aut Emanuele Trucco verfasserin aut Tom MacGillivray verfasserin aut Kristiina Rannikmae verfasserin aut Albert Tenesa verfasserin aut Erola Pairo-Castineira verfasserin aut Miguel O. Bernabeu verfasserin aut In Communications Biology Nature Portfolio, 2018 6(2023), 1, Seite 13 (DE-627)101369080X 23993642 nnns volume:6 year:2023 number:1 pages:13 https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 kostenfrei https://doi.org/10.1038/s42003-023-04836-9 kostenfrei https://doaj.org/toc/2399-3642 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2023 1 13
language	English
source	In Communications Biology 6(2023), 1, Seite 13 volume:6 year:2023 number:1 pages:13
sourceStr	In Communications Biology 6(2023), 1, Seite 13 volume:6 year:2023 number:1 pages:13
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Biology (General)
isfreeaccess_bool	true
container_title	Communications Biology
authorswithroles_txt_mv	Ana Villaplana-Velasco @@aut@@ Marie Pigeyre @@aut@@ Justin Engelmann @@aut@@ Konrad Rawlik @@aut@@ Oriol Canela-Xandri @@aut@@ Claire Tochel @@aut@@ Frida Lona-Durazo @@aut@@ Muthu Rama Krishnan Mookiah @@aut@@ Alex Doney @@aut@@ Esteban J. Parra @@aut@@ Emanuele Trucco @@aut@@ Tom MacGillivray @@aut@@ Kristiina Rannikmae @@aut@@ Albert Tenesa @@aut@@ Erola Pairo-Castineira @@aut@@ Miguel O. Bernabeu @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	101369080X
id	DOAJ090525108
language_de	englisch
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callnumber-first	Q - Science
author	Ana Villaplana-Velasco
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topic_title	QH301-705.5 Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
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title	Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
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title_full	Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
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author_browse	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
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title_sort	fine-mapping of retinal vascular complexity loci identifies notch regulation as a shared mechanism with myocardial infarction outcomes
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title_auth	Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes
url	https://doi.org/10.1038/s42003-023-04836-9 https://doaj.org/article/9575d863a72646d1847fcdfd16c30071 https://doaj.org/toc/2399-3642
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Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes

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