Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants.
Commun Biol, 2020/12/11;3(1):762.
Jiang X[1], Dellepiane N[1], Pairo-Castineira E[1], Boutin T[1], Kumar Y[1], Bickmore WA[1], Vitart V[2]
Affiliations
PMID: 33311554DOI: 10.1038/s42003-020-01497-w
Impact factor: 6.548
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.
MeSH terms
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
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