| Title: | Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants |
| Journal: | Communications Biology |
| Published: | 11 Dec 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33311554/ |
| DOI: | https://doi.org/10.1038/s42003-020-01497-w |
| URL: | https://www.nature.com/articles/s42003-020-01497-w.pdf |
| Citations: | 8 (5 in last 2 years) as of 8 Aug 2024 |
Publication 4857
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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.16 Keywords
- Alleles
- Chromosome Mapping
- Computational Biology
- Corneal Diseases
- Databases, Genetic
- Female
- Gene Expression Regulation
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Molecular Sequence Annotation
- Organ Specificity
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- United Kingdom
7 Authors
- Xinyi Jiang
- Nefeli Dellepiane
- Erola Pairo-Castineira
- Thibaud Boutin
- Yatendra Kumar
- Wendy A. Bickmore
- Veronique Vitart
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