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Multi-ancestry GWAS of Fuchs corneal dystrophy highlights roles of laminins, collagen, and endothelial cell regulation.
- Source :
-
Research square [Res Sq] 2023 May 03. Date of Electronic Publication: 2023 May 03. - Publication Year :
- 2023
-
Abstract
- 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.
Details
- Language :
- English
- Database :
- MEDLINE
- Journal :
- Research square
- Accession number :
- 37205546
- Full Text :
- https://doi.org/10.21203/rs.3.rs-2762003/v1