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 (N_total=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (β_s.d.=-0.109; SE=0.015; P=2.39×10-¹³) and in COL4A2 was rs7991229 (β_s.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.

Figure 1.

Study Design. Natural log-transformed data—TortA, TortAmax, TortV, TortVmax, u is the genetic value for each subject under a random-effects model, covariance amongst subjects assumed to be proportionate to the genomic relationship matrix. All Croatia indicates Croatia island of Korcula, Croatia-Split; AVR, arteriole-to-venule ratio; CRAE, Central Retinal Arteriolar Equivalent; CRVE, Central Retinal Venular Equivalent; GoDARTS, Genetics of Diabetes Audit and Research in Tayside; LBC1936, Lothian Birth Cohorts 1936; ODradius, Optic Disc Radius; ORCADES, Orkney Complex Disease Study; PC, principal components; TortA, retinal arteriolar tortuosity; TortAmax, maximum retinal arteriolar tortuosity; TortV, retinal venular tortuosity; and TortVmax, maximum retinal arteriolar tortuosity.

Figure 2.

Manhattan plots for meta-analysis of genome-wide association results from 2 independent discovery cohorts. A, The results for the arteriolar tortuosity (TortA) and (B) represents the results for the venular tortuosity trait (TortV). The blue and red horizontal lines indicate the suggestive and genome-wide significance threshold (P<5×10⁻⁸), respectively.

Figure 3.

Regional association and recombination plots of variants that reached P value <5×10^-7 in the meta-analysis of the 2 discovery study cohorts (GoDARTS and ORCADES). A, Lead SNP for TortA; B, lead SNP for TortV. Each plot was created using LocusZoom for the lead single-nucleotide polymorphism (SNP) in genomic region 400 kb in either side of the significant signal. Blue spikes represent the estimated recombination rates. Color scale (high to low r²) circles depicts the pairwise correlation (r²) between lead SNP and other SNPs in the loci. The lead SNP in that region is indicated by purple color solid diamond, and gene annotations in this region are shown in the bottom. GoDARTS indicates Genetics of Diabetes Audit and Research in Tayside; and ORCADES, Orkney Complex Disease Study.

Figure 4.

Forest plots for the genome-wide significant hits in overall meta-analysis. A, rs7991229 for TortA; B, rs1808382 for TortV. The plots represent standardized β (β_sd) and SE from GoDARTS (Genetics of Diabetes Audit and Research in Tayside), ORCADES (Orkney Complex Disease Study), LBC1936 (Lothian Birth Cohorts 1936), Croatia-Korcula Split, and meta-analysis study. Standardized β estimate: change in natural log-transformed retinal tortuosity traits for each copy of the effect allele.