Abstract
Corneal resistance factor (CRF) is altered during corneal diseases progression. Genome-wide-association studies (GWAS) indicated potential CRF and disease genetics overlap. Here, we characterise 135 CRF loci following GWAS in 76029 UK Biobank participants. Enrichment of extra-cellular matrix gene-sets, genetic correlation with corneal thickness (70% (SE = 5%)), reported keratoconus risk variants at 13 loci, all support relevance to corneal stroma biology. Fine-mapping identifies a subset of 55 highly likely causal variants, 91% of which are non-coding. Genomic features enrichments, using all associated variants, also indicate prominent regulatory causal role. We newly established open chromatin landscapes in two widely-used human cornea immortalised cell lines using ATAC-seq. Variants associated with CRF were significantly enriched in regulatory regions from the corneal stroma-derived cell line and enrichment increases to over 5 fold for variants prioritised by fine-mapping-including at GAS7, SMAD3 and COL6A1 loci. Our analysis generates many hypotheses for future functional validation of aetiological mechanisms.
Highlights
Corneal resistance factor (CRF) is altered during corneal diseases progression
Variant effects were consistent between this analysis and a Genomewide-association studies (GWAS) performed in a smaller set of European non-British participants (N = 10,130) (Supplementary Fig. 1, Supplementary Data 2), with the exception of strong but opposite-direction effects for the lead, low-frequency variant, rs112108520 at the ETS1 locus
The Fuchs endothelial corneal dystrophy (FECD) risk alleles of representative SNPs at these three sites were all associated with decreasing corneal resistance, and their effects on FECD risk appear correlated with their effect on CRF (Supplementary Fig. 2)
Summary
Corneal resistance factor (CRF) is altered during corneal diseases progression. Genomewide-association studies (GWAS) indicated potential CRF and disease genetics overlap. Genome-wide association studies (GWAS) for measurements acquired in heathy individuals—corneal thickness[3,4,5,6,7,8], curvature[9,10], resistance factor and hysteresis[11], endothelial cells shape, and density7—showed potential to elucidate molecular events shaping these traits and associated disease risks. Statistical methods have emerged to narrow-down the genetic variants most likely to cause observed associations, with high throughput[12] Those can provide single-variant resolution, unlocking mechanism hypothesis, even if only for a small fraction of GWAS loci[13]. To explore this avenue, we leveraged the availability in >75-,000 UK Biobank (UKBB) participants of corneal resistance factor (CRF) measures. The strong CRF genetic associations at ANAPC1 and TCF47,11, major loci for respectively endothelial cell density[7] and Fuchs endothelial corneal dystrophy (FECD)[20], emphasize a relevance to corneal endothelium health not prominent in the CCT GWAS results
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