Background: Genome-wide association studies have identified the CDC7-TGFBR3 intergenic region on chromosome 1 to be strongly associated with optic disc area size. The mechanism of its function remained unclear until new data on eQTL markers emerged from the Genotype-Tissue Expression project. The target region was found to contain a strong silencer of the distal (800 kb) Transcription Factor (TF) gene GFI1 (Growth Factor Independent Transcription Repressor 1) specifically in neuroendocrine cells (pituitary gland). GFI1 has also been reported to be involved in the development of sensory neurons and hematopoiesis. Therefore, GFI1, being a developmental gene, is likely to affect optic disc area size by altering the expression of the associated genes via long-range interactions.
Results: Distribution of haplotypes in the putative enhancer region has been assessed using the data on four continental supergroups generated by the 1000 Genomes Project. The East Asian (EAS) populations were shown to manifest a highly homogenous unimodal haplotype distribution pattern within the region with the major haplotype occurring with the frequency of 0.9. Another European specific haplotype was observed with the frequency of 0.21. The major haplotype appears to be involved in silencing GFI1repressor gene expression, which might be the cause of increased optic disc area characteristic of the EAS populations. The enhancer/eQTL region overlaps AluJo element, which implies that this particular regulatory element is primate-specific and confined to few tissues.
Conclusion: Population specific distribution of GFI1 enhancer alleles may predispose certain ethnic groups to glaucoma.
Keywords: 1000GP; Alu; CDC7; Enhancers; GFI1; GTEx; GWAS; Glaucoma; Optic disc size; TGFB3.