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Purpose: To assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). Methods: We developed a FECD case-control algorithm based on structured EHR data and accuracy confirmed by individual review of charts at three VA Medical Centers. This algorithm was applied to the Department of Veterans Affairs Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes and laboratory values were extracted. Single and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. Results: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and non-ocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for four being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. Conclusions: Female gender, European ancestry and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes as well as altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. DM may modify FECD onset and encourage progression among susceptible individuals, suggesting that optimizing glucose control may be an effective preventative for FECD.

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Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular pathophysiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program (MVP) and meta-analyzed with the previous largest FECD GWAS, finding twelve significant loci (eight novel). We further confirmed the TCF4 locus in admixed African and Hispanic/Latino ancestries, and found an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and co-localization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.