Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, Brisbane, Herston, QLD 4006, Australia.
Max Kelsen, Brisbane, Spring Hill, QLD 4000, Australia.
Am J Hum Genet. 2021 Jul 1;108(7):1204-1216. doi: 10.1016/j.ajhg.2021.05.005. Epub 2021 Jun 1.
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.
视神经头杯状，这是一种高度遗传的特征，是青光眼视神经病变的标志。两个关键参数是垂直杯盘比（VCDR）和垂直盘直径（VDD）。然而，手动评估通常准确性较差，且耗时。在这里，我们展示了卷积神经网络模型可以准确估计来自 UK Biobank 和独立研究（加拿大老龄化纵向研究）的 282100 张图像的 VCDR 和 VDD，从而能够进行跨种族的流行病学研究，并为这些视神经头参数发现新的遗传因素。使用人工智能方法，我们对 VCDR 和 VDD 的分布进行了系统比较，并将其与不同遗传决定的种族中的眼压和青光眼诊断进行了比较，这为东亚正常眼压性青光眼的高发病率提供了一个解释。然后，我们使用大量的人工智能分级来对视神经头参数进行更强大的全基因组关联研究（GWAS）。使用基于人工智能的分级方法，VCDR 和 VDD 的遗传率估计值增加了约 50%。我们的 GWAS 确定了 200 多个与 VCDR 和 VDD 相关的位点（是以前研究中数量的两倍），并揭示了数十个生物学途径；我们发现的许多位点也会增加青光眼的风险。
