Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA

• Published in: American journal of human genetics Vol. 108; no. 7; pp. 1204 - 1216
• Main Authors: Han, Xikun, Steven, Kaiah, Qassim, Ayub, Marshall, Henry N., Bean, Cameron, Tremeer, Michael, An, Jiyuan, Siggs, Owen M., Gharahkhani, Puya, Craig, Jamie E., Hewitt, Alex W., Trzaskowski, Maciej, MacGregor, Stuart
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021; Elsevier
• Subjects: Adult; Aged; Algorithms; Artificial Intelligence; CLSA; Female; Genome-Wide Association Study; glaucoma; Glaucoma - diagnosis; Glaucoma - genetics; Glaucoma - pathology; GWAS; Humans; Image Processing, Computer-Assisted; Inheritance Patterns; Intraocular Pressure; Male; Middle Aged; Nerve Net; Optic Disk - diagnostic imaging; Optic Disk - pathology; optic nerve head; Photography; Polymorphism, Single Nucleotide; Risk Factors; UK Biobank; image; GWAS; glaucoma; CLSA; optic nerve head; UK Biobank; artificial intelligence
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2021.05.005

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.