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.

福克斯内皮性角膜营养不良（FECD）是角膜移植的主要适应症，但其分子病因学仍知之甚少。我们对百万退伍军人计划中的 FECD 进行了全基因组关联研究 (GWAS)，随后对之前最大的 FECD GWAS 进行了多祖先荟萃分析，总共涉及 3970 例病例和 333,794 名对照。我们确认了前面的四个基因座，并确定了八个新基因座：SSBP3、THSD7A、LAMB1、PIDD1、RORA、HS3ST3B1、LAMA5和COL18A1。我们进一步确认了GWAS 中非洲裔和西班牙裔/拉丁裔混合血统的TCF4基因座，并显示FECD 病例中TCF4处欧洲血统单倍型的富集。这些新的关联包括层粘连蛋白基因LAMA5和LAMB1中的低频错义变异，它们与之前报道的LAMC1一起形成层粘连蛋白-511 (LM511)。通过同源性验证的 AlphaFold 2 蛋白质模型表明，LAMA5和LAMB1的突变可能通过改变域间相互作用或细胞外基质结合来破坏 LM511 的稳定性。最后，全表型关联扫描和共定位分析表明，TCF4 CTG18.1 三核苷酸重复扩增导致角膜内皮离子转运失调，并对肾功能产生多效性影响。