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:10.1042/bj20031154

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

Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (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 two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=−0.109; standard error (SE) =0.015; P=2.39×10−13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66×10−12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into cardiovascular diseases.

Original language	English
Publisher	BioRxiv
DOIs	https://doi.org/10.1042/bj20031154
Publication status	Published - 20 Jun 2018

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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10.1042/bj20031154Licence: CC BY-ND

PreprintSubmitted manuscript, 738 KBLicence: CC BY-ND

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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. (2018). Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease. BioRxiv. https://doi.org/10.1042/bj20031154

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

abstract = "Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (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 two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=−0.109; standard error (SE) =0.015; P=2.39×10−13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66×10−12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into 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 = "2018",

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day = "20",

doi = "10.1042/bj20031154",

language = "English",

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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 2018 'Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease' BioRxiv. https://doi.org/10.1042/bj20031154

TY - UNPB

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 - 2018/6/20

Y1 - 2018/6/20

N2 - Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (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 two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=−0.109; standard error (SE) =0.015; P=2.39×10−13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66×10−12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into cardiovascular diseases.

AB - Structural variation in retinal blood vessels is associated with global vascular health in humans and may provide a readily accessible indicator of several diseases of vascular origin. Increasing evidence suggests variation in retinal vasculature is highly heritable. This study aimed to identify genetic determinants of retinal vascular traits. We reported a meta-analysis of genome-wide association studies (GWAS) for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the Genetics of Diabetes Audit and Research in Tayside (GoDARTS) (n=1736) and the Orkney Complex Disease Study (ORCADES) (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 two loci were subsequently confirmed in three independent cohorts (n=1413). In the combined analysis in ACTN4/CAPN12 the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=−0.109; standard error (SE) =0.015; P=2.39×10−13) and in COL4A2 it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66×10−12). Notably, the ACTN4/CAPN12 locus associated with retinal TortV is also associated with coronary artery disease and heart rate. Our findings demonstrate the contribution of genetics in retinal tortuosity traits, and provide new insights into 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 - 10.1042/bj20031154

DO - 10.1042/bj20031154

M3 - Preprint

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

PB - BioRxiv

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)