June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Analyses of whole genome sequencing and imputed datasets identify a rare variant associated with intraocular pressure within the TMCO1 gene
Author Affiliations & Notes
  • Abhishek Nag
    Dept of Twin Research, King's College London, London, United Kingdom
  • Henriet Springelkamp
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Adriana I Iglesias
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Wishal Ramdas
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Najaf Amin
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Caroline C W Klaver
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Cornelia M van Duijn
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Christopher J Hammond
    Dept of Twin Research, King's College London, London, United Kingdom
  • Pirro G Hysi
    Dept of Twin Research, King's College London, London, United Kingdom
  • Footnotes
    Commercial Relationships Abhishek Nag, None; Henriet Springelkamp, None; Adriana Iglesias, None; Wishal Ramdas, None; Najaf Amin, None; Caroline Klaver, None; Cornelia van Duijn, None; Christopher Hammond, None; Pirro Hysi, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4379. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Abhishek Nag, Henriet Springelkamp, Adriana I Iglesias, Wishal Ramdas, Najaf Amin, Caroline C W Klaver, Cornelia M van Duijn, Christopher J Hammond, Pirro G Hysi; Analyses of whole genome sequencing and imputed datasets identify a rare variant associated with intraocular pressure within the TMCO1 gene. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4379.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×