Deep Learning of the Retina Enables Phenome- and Genome-wide Analyses of the Microvasculature


Zekavat SM, Raghu VK, Trinder M, Ye Y, Koyama S, Honigberg MC, Yu Z, Pampana A, Urbut S, Haidermota S, O'Regan DP, Zhao H, Ellinor PT, Segrè AV, Elze T, Wiggs JL, Martone J, Adelman RA, Zebardast N, Del Priore L, Wang JC, Natarajan P. Deep Learning of the Retina Enables Phenome- and Genome-wide Analyses of the Microvasculature. Circulation 2021;

Date Published:

2021 Nov 08


Background: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health as well as tumorigenesis. The retinal fundus is a window for human in vivo non-invasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. Methods: We utilized 97,895 retinal fundus images from 54,813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated fractal dimension (FD) as a measure of vascular branching complexity, and vascular density. We associated these indices with 1,866 incident ICD-based conditions (median 10y follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Results: Low retinal vascular FD and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular FD and density identified 7 and 13 novel loci respectively, which were enriched for pathways linked to angiogenesis (e.g., VEGF, PDGFR, angiopoietin, and WNT signaling pathways) and inflammation (e.g., interleukin, cytokine signaling). Conclusions: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights on genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health records, biomarker, and genetic data to inform risk prediction and risk modification.

Last updated on 12/01/2021