The human retina is a complex multi-layered tissue which offers a unique window into systemic health and disease. Optical coherence tomography (OCT) is widely used in eye care and allows the non-invasive, rapid capture of retinal measurements in exquisite detail. We conducted genome- and phenome-wide analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed phenome-wide association analyses, associating retinal thicknesses with 1,866 incident ICD-based conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association analyses, identifying inherited genetic markers which influence the retina, and replicated our associations among 6,313 individuals from the LIFE-Adult Study. And lastly, we performed comparative association of phenome- and genome- wide associations to identify putative causal links between systemic conditions, retinal layer thicknesses, and ocular disease. Independent associations with incident mortality were detected for photoreceptor thinning and ganglion cell complex thinning. Significant phenotypic associations were detected between retinal layer thinning and ocular, neuropsychiatric, cardiometabolic and pulmonary conditions. Genome-wide association of retinal layer thicknesses yielded 259 loci. Consistency between epidemiologic and genetic associations suggested putative causal links between thinning of the retinal nerve fiber layer with glaucoma, photoreceptor segment with AMD, as well as poor cardiometabolic and pulmonary function with PS thinning, among other findings. In conclusion, retinal layer thinning predicts risk of future ocular and systemic disease. Furthermore, systemic cardio-metabolic-pulmonary conditions promote retinal thinning. Retinal imaging biomarkers, integrated into electronic health records, may inform risk prediction and potential therapeutic strategies.

The authors have declared no competing interest.

N.Z. is supported by the National Eye Institute (NEI) 1K23EY032634. P.N. is supported by a Hassenfeld Scholar Award from the Massachusetts General Hospital, and grants from the National Heart, Lung, and Blood Institute (R01HL1427, R01HL148565, and R01HL148050). S.M.Z. is supported by the Leducq Early Career Investigator Award and the NIH National Heart, Lung, and Blood Institute (1F30HL149180-01). J.L.W. is supported in part by NEI (R01EY020928, R01EY022305, R01EY031820, R01EY032559). T. E. is supported by grants from NIH (NIH R21 EY030631, NIH R01 EY030575, NIH P30 EY003790). This research was supported by LIFE Leipzig Research Center for Civilization Diseases, Leipzig University (LIFE is funded by the EU, the European Social Fund, the European Regional Development Fund, and Free State Saxonys excellence initiative; project numbers: 713-241202, 14505/2470, 14575/2470). F.G.R. was supported by the German Research Foundation (grant number DFG 497989466). The opinions expressed by the authors are their own and this material should not be interpreted as representing the official viewpoint of the National Institutes of Health or National Eye Institute.

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UK Biobank data use was approved by the Massachusetts General Hospital Institutional Review Board (protocol 2021P002040) and facilitated through UK Biobank Applications 7089 and 50211. The LIFE-Adult Study replication was approved by the Ethics Committee of the Medical Faculty of Leipzig University, and the research was conducted in accordance with the Declaration of Helsinki.

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