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A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

ABSTRACT: Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show 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, validated through homology, 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 colocalization 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.

SUBMITTER: Gorman BR

PROVIDER: S-EPMC10998918 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

Gorman Bryan R BR Francis Michael M Nealon Cari L CL Halladay Christopher W CW Duro Nalvi N Markianos Kyriacos K Genovese Giulio G Hysi Pirro G PG Choquet Hélène H Afshari Natalie A NA Li Yi-Ju YJ Gaziano J Michael JM Hung Adriana M AM Wu Wen-Chih WC Greenberg Paul B PB Pyarajan Saiju S Lass Jonathan H JH Peachey Neal S NS Iyengar Sudha K SK

Communications biology 20240406 1

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We ...[more]

PMID: 38582945

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Project description:PurposeTo develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography.DesignCross-sectional study.ParticipantsForty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK.MethodsScheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT.Main outcome measuresPredictive power (R 2) and mean difference between predicted and observed change in CCT.ResultsThe gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R 2 = 0.80; 95% confidence interval [CI], 0.71-0.89) and the mean difference between predicted and observed change was, by definition, 0 μm. When the same 5 parameters were fit to the validation group, the model performed very highly (R 2 = 0.89; 95% CI, 0.84-0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R 2 = 0.78; 95% CI, 0.68-0.88), and the mean difference was 4 μm (predicted minus observed).ConclusionsScheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

Dataset Information

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

Publications

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

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