Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease

Abirami Veluchamy; Lucia Ballerini; Veronique Vitart; Katharina E. Schraut; Mirna Kirin; Harry Campbell; Peter K. Joshi; Devanjali Relan; Sarah  Harris; Suraj S . Vaidya; Baljean Dhillon; Kaixin Zhou; Ewan Pearson; Caroline Hayward; Ozren Polašek; Ian J. Deary; Thomas J. MacGillivray; James  F. Wilson; Manuel Trucco; Colin Palmer; Alexander Doney

doi:10.1161/ATVBAHA.119.312552

Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease

Abirami Veluchamy, Lucia Ballerini, Veronique Vitart, Katharina E. Schraut, Mirna Kirin, Harry Campbell, Peter K. Joshi, Devanjali Relan, Sarah Harris, Suraj S . Vaidya, Baljean Dhillon, Kaixin Zhou, Ewan Pearson, Caroline Hayward, Ozren Polašek, Ian J. Deary, Thomas J. MacGillivray, James F. Wilson, Manuel Trucco, Colin Palmer (Lead / Corresponding author)Alexander Doney (Lead / Corresponding author)

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Abstract

Objective: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (βs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (βs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation.

Conclusions: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.

Original language	English
Pages (from-to)	2542-2552
Number of pages	11
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	39
Issue number	12
Early online date	10 Oct 2019
DOIs	https://doi.org/10.1161/ATVBAHA.119.312552
Publication status	Published - Dec 2019

Keywords

atrial fibrillation
biomarkers
cardiovascular diseases
genome-wide association study
heart rate
retina

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/ATVBAHA.119.312552Licence: CC BY

Final Published VersionFinal published version, 594 KBLicence: CC BY

Cite this

Veluchamy, A., Ballerini, L., Vitart, V., Schraut, K. E., Kirin, M., Campbell, H., Joshi, P. K., Relan, D., Harris, S., Vaidya, S. S. ., Dhillon, B., Zhou, K., Pearson, E., Hayward, C., Polašek, O., Deary, I. J., MacGillivray, T. J., Wilson, J. F., Trucco, M., ... Doney, A. (2019). Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(12), 2542-2552. https://doi.org/10.1161/ATVBAHA.119.312552

@article{f114978fe7934104849707ad4c073056,

title = "Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease",

abstract = "Objective: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (βs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (βs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation.Conclusions: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.",

keywords = "atrial fibrillation, biomarkers, cardiovascular diseases, genome-wide association study, heart rate, retina",

author = "Abirami Veluchamy and Lucia Ballerini and Veronique Vitart and Schraut, {Katharina E.} and Mirna Kirin and Harry Campbell and Joshi, {Peter K.} and Devanjali Relan and Sarah Harris and Vaidya, {Suraj S .} and Baljean Dhillon and Kaixin Zhou and Ewan Pearson and Caroline Hayward and Ozren Pola{\v s}ek and Deary, {Ian J.} and MacGillivray, {Thomas J.} and Wilson, {James F.} and Manuel Trucco and Colin Palmer and Alexander Doney",

note = "The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) was funded by The Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extract Phenotype collection for LBC1936 was supported by Age UK (The Disconnected Mind project). Genotyping for LBC1936 was funded by the BBSRC (BB/F019394/1). The LBC1936 work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. The Croatia- Kor{\v c}ula and Croatia-Split study were funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947), European Commission Framework 7 project BBMRI-LPC (FP7 313010), the Republic of Croatia Ministry of Science, Education and Sports research grant (216-1080315-0302) and the Croatian Science Foundation (grant 8875). The SNP genotyping for the Kor{\v c}ula cohort was performed in Helmholtz Zentrum M{\"u}nchen, Neuherberg, Germany. VAMPIRE team: Parts of the VAMPIRE software and its use for measuring the image set described here was funded by the Leverhulme Trust project RPG-419 “Discovery of retinal biomarkers for genetics with large cross-linked data sets”. VAMPIRE 3.1 has been further developed under funding from EPSRC (EPSRC EP/M005976/1) and the EU (“REVAMMAD” FP7-PEOPLE ITN, grant agreement 316990). For the analysis of the association of the identified genetic variants with heart rate, this research has been conducted using the UK Biobank Resource under Application Number 20405.",

year = "2019",

month = dec,

doi = "10.1161/ATVBAHA.119.312552",

language = "English",

volume = "39",

pages = "2542--2552",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

Veluchamy, A, Ballerini, L, Vitart, V, Schraut, KE, Kirin, M, Campbell, H, Joshi, PK, Relan, D, Harris, S, Vaidya, SS, Dhillon, B, Zhou, K, Pearson, E, Hayward, C, Polašek, O, Deary, IJ, MacGillivray, TJ, Wilson, JF, Trucco, M , Palmer, C & Doney, A 2019, 'Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 39, no. 12, pp. 2542-2552. https://doi.org/10.1161/ATVBAHA.119.312552

TY - JOUR

T1 - Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease

AU - Veluchamy, Abirami

AU - Ballerini, Lucia

AU - Vitart, Veronique

AU - Schraut, Katharina E.

AU - Kirin, Mirna

AU - Campbell, Harry

AU - Joshi, Peter K.

AU - Relan, Devanjali

AU - Harris, Sarah

AU - Vaidya, Suraj S .

AU - Dhillon, Baljean

AU - Zhou, Kaixin

AU - Pearson, Ewan

AU - Hayward, Caroline

AU - Polašek, Ozren

AU - Deary, Ian J.

AU - MacGillivray, Thomas J.

AU - Wilson, James F.

AU - Trucco, Manuel

AU - Palmer, Colin

AU - Doney, Alexander

N1 - The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) was funded by The Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extract Phenotype collection for LBC1936 was supported by Age UK (The Disconnected Mind project). Genotyping for LBC1936 was funded by the BBSRC (BB/F019394/1). The LBC1936 work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. The Croatia- Korčula and Croatia-Split study were funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947), European Commission Framework 7 project BBMRI-LPC (FP7 313010), the Republic of Croatia Ministry of Science, Education and Sports research grant (216-1080315-0302) and the Croatian Science Foundation (grant 8875). The SNP genotyping for the Korčula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. VAMPIRE team: Parts of the VAMPIRE software and its use for measuring the image set described here was funded by the Leverhulme Trust project RPG-419 “Discovery of retinal biomarkers for genetics with large cross-linked data sets”. VAMPIRE 3.1 has been further developed under funding from EPSRC (EPSRC EP/M005976/1) and the EU (“REVAMMAD” FP7-PEOPLE ITN, grant agreement 316990). For the analysis of the association of the identified genetic variants with heart rate, this research has been conducted using the UK Biobank Resource under Application Number 20405.

PY - 2019/12

Y1 - 2019/12

N2 - Objective: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (βs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (βs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation.Conclusions: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.

AB - Objective: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (βs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (βs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation.Conclusions: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.

KW - atrial fibrillation

KW - biomarkers

KW - cardiovascular diseases

KW - genome-wide association study

KW - heart rate

KW - retina

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U2 - 10.1161/ATVBAHA.119.312552

DO - 10.1161/ATVBAHA.119.312552

M3 - Article

C2 - 31597446

SN - 1079-5642

VL - 39

SP - 2542

EP - 2552

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 12

ER -

Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Scotland India Diabetes Health Informatics Unit (joint with Madras Diabetes Research Foundation)

Multi-modal Retinal Biomarkers for Vascular Dementia; Developing and Enabling Image Analysis Tools (Joint with University of Edinburgh)