Analyses of whole genome sequencing and imputed datasets identify a rare variant associated with intraocular pressure within the TMCO1 gene

Abstract

Purpose: Intra-ocular pressure (IOP) is the most important risk factor for glaucoma, and IOP-lowering medication remains the mainstay of current glaucoma treatment. To date, several common variants (>5% frequency) have been identified in genome-wide association studies (GWAS) in relationship to IOP. This work explores the hypothesis that low frequency variants underlie part of the unexplained heritability of IOP.

Methods: 1150 subjects from the TwinsUK cohort with IOP data had their whole genome sequenced as a part of the UK10K project. An additional panel comprising of 14,018 subjects with IOP data were imputed based on a combination of the UK10K and the 1000 Genomes reference sequences. This panel included a second set of subjects from the TwinsUK (fully unrelated to the sequenced ones) [N=450] that had not been sequenced but had genotype data; and subjects from the three Rotterdam studies (RSI, RSII and RSIII) [N=11,097] and the Erasmus Rucphen Family (ERF) study [N=2,471]. Association testing between IOP (adjusted for age and sex) and genotypes was performed using linear regression models. A fixed-effect inverse variance meta-analysis was performed on the summary of results from all the datasets.

Results: An intronic variant (rs35310077) in the gene TMCO1 at the locus 1q24.1 was significantly associated with IOP (p = 4.6 x 10^-9) at the conventional genome-wide significance threshold (p < 5 x 10^-8). rs35310077, which had an effective minor allele frequency of 0.9 %, had an effect size (b) of 1.18 mm Hg in the meta-analysis. rs35310077 was in low LD (r² < 0.2) with the SNPs at the previously reported locus in TMCO1 associated with IOP. Conditional analysis for the most significant SNP at the previously reported locus (rs7555523) showed that rs35310077 had an effect on IOP (adjusted b = 0.97 mm Hg; p = 3.48 x 10^-6) that was independent of the previously reported association.

Conclusions: Our study supports the hypothesis that rare variants with intermediate effect size might determine part of the genetic architecture of IOP. Identification of a rare variant in TMCO1, a gene that has previously been associated with IOP / glaucoma, further affirms the role of this gene in regulating IOP and thus determining glaucoma susceptibility.