Novel locus influencing retinal venular tortuosity is also associated with risk of coronary artery disease
Authors: Veluchamy Abirami , Ballerini Lucia , Vitart Veronique , Schraut Katharina E , Kirin Mirna , Campbell Harry , Joshi Peter K , Relan Devanjali , Harris Sarah , Brown Ellie , Vaidya Suraj K , Dhillon Bal , Zhou Kaixin , Pearson Ewan R , Hayward Caroline , Polasek Ozren , Deary Ian J , MacGillivray Thomas , Wilson James F , Trucco Emanuele , Palmer Colin NA , Doney Alexander S F 
Published: April 2017

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 inACTN4/CAPN12the lead single nucleotide polymorphism (SNP) was rs1808382 (n=4507; Beta=−0.109; standard error (SE) =0.015; P=2.39×10−13) and inCOL4A2it was rs7991229 (n=4507; Beta=0.103; SE=0.015; P=4.66×10−12). Notably, theACTN4/CAPN12locus associated with retinalTortVis 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.

Author Summary

Retinal vascular features are associated with wide range of diseases related to vascular health and provide an opportunity to understand early structural changes in vasculature which may help to predict disease risk. Emerging evidence indicates that retinal tortuosity traits are both associated with vascular health and highly heritable. However, the genetic architecture of retinal vascular tortuosity has not been investigated. We therefore performed a genome-wide association study on retinal arteriolar tortuosity (TortA) and retinal venular tortuosity trait (TortV) using data from two independent discovery cohorts of 3094 individuals of European-heritage. We found a novel associations at 19q13 (ACTN4/CAPN12) forTortV, and one at 13q34 (COL4A2) forTortAat discovery stage and validated in three independent cohorts. A significant association was subsequently found between lead SNPs at 19q13 and coronary artery disease, cardiovascular vascular risk factors and heart rate. We also performed genome-wide association studies for retinal vascular calibres and optic disc radius (ODradius) and replicated previously reported locus at 10q21.3 forODradius. Our findings highlight genetic impacts on retinal venular tortuosity and it is association with cardiovascular disease. This may provide a molecular pathophysiological foundation for use of retinal vascular traits as biomarkers for cardiovascular diseases.