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We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (<jats:italic>N<\/jats:italic>= 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.<\/jats:p>","DOI":"10.1126\/scitranslmed.adg4517","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T18:58:53Z","timestamp":1706122733000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":55,"title":["Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4026-8944","authenticated-orcid":true,"given":"Seyedeh Maryam","family":"Zekavat","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, 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