Mechanosensitive ion channel gene survey suggests potential roles in primary open angle glaucoma

Abstract

Although glaucoma is a disease modulated by eye pressure, the mechanisms of pressure sensing in the eye are not well understood. Here, we investigated associations between mechanosensitive ion channel gene variants and primary open-angle glaucoma (POAG). Common (minor allele frequency > 5%) single nucleotide polymorphisms located within the genomic regions of 20 mechanosensitive ion channel genes in the K2P, TMEM63, PIEZO and TRP channel families were assessed using genotype data from the NEIGHBORHOOD consortium of 3853 cases and 33,480 controls. Rare (minor allele frequency < 1%) coding variants were assessed using exome array genotyping data for 2606 cases and 2606 controls. Association with POAG was analyzed using logistic regression adjusting for age and sex. Two rare PIEZO1 coding variants with protective effects were identified in the NEIGHBOR dataset: R1527H, (OR 0.17, P = 0.0018) and a variant that alters a canonical splice donor site, g.16-88737727-C-G Hg38 (OR 0.38, P = 0.02). Both variants showed similar effects in the UK Biobank and the R1527H also in the FinnGen database. Several common variants also reached study-specific thresholds for association in the NEIGHBORHOOD dataset. These results identify novel variants in several mechanosensitive channel genes that show associations with POAG, suggesting that these channels may be potential therapeutic targets.

Figure 1

Consequence of PIEZO1 canonical donor splice variant (16-88737727-C-G). The C > G change disrupts the canonical donor splice sequence GT (the minus strand is shown in the image), leading to retention of the short intron (81 base pairs). A stop codon is not encountered in the reading frame, and as a result 27 amino acids are included in the polypeptide sequence. The amino acids potentially included in the protein are listed below the sequence at the top of the image. Image is rendered from the UCSC genome browser (https://genome.ucsc.edu/).

Figure 2

Expression of selected genes with interesting associations with POAG in ocular tissues. Single-cell and single-nucleus sequencing data were extracted for anterior segment cell types, neuronal cell types in the retina including retinal ganglion cells, and non-neuronal retinal cell types. Dot plots show expression of selected genes in anterior segment and retinal cell types. Dot size indicates fraction of expressing cells, and color indicates mean expression in expressing cells.