April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Identification of disease-associated genome variants in regulatory regions using exome sequencing in 295 POAG cases
Author Affiliations & Notes
  • Terry Gaasterland
    Institute for Genomic Medicine, Univ of California San Diego, La Jolla, CA
    Shiley Eye Center, Univ of California San Diego, La Jolla, CA
  • Douglas E Gaasterland
    Sanford Consortium for Regenerative Medicine, Univ of California San Diego, La Jolla, CA
  • Lee E Edsall
    Graduate Program in Genetics and Genomics, Duke University, Durham, CA
    Duke Center for Human Genetics, Duke University, Durham, NC
  • Amy N Dubinsky
    Sanford Consortium for Regenerative Medicine, Univ of California San Diego, La Jolla, CA
  • Kuan-Fu Ding
    Bioinformatics and Systems Biology Graduate Program, Univ of California San Diego, La Jolla, CA
  • Steven Head
    Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA
  • Karl H Willert
    Sanford Consortium for Regenerative Medicine, Univ of California San Diego, La Jolla, CA
  • Consortium The NEIGHBOR
    Massachusetts Eye and Ear Institute, Harvard, Boston, MA
    Duke Center for Human Genetics, Duke University, Durham, NC
  • Footnotes
    Commercial Relationships Terry Gaasterland, None; Douglas Gaasterland, None; Lee Edsall, None; Amy Dubinsky, None; Kuan-Fu Ding, None; Steven Head, None; Karl Willert, None; Consortium The NEIGHBOR, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3792. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Terry Gaasterland, Douglas E Gaasterland, Lee E Edsall, Amy N Dubinsky, Kuan-Fu Ding, Steven Head, Karl H Willert, Consortium The NEIGHBOR, ; Identification of disease-associated genome variants in regulatory regions using exome sequencing in 295 POAG cases. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3792.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: To discover disease-associated genome variants in coding or regulatory regions of genes.

Methods: DNA collected from 295 affected individuals was enriched using probes designed to capture coding exons, untranslated regions (UTR), flanking intron, and proximal promoters. Patient samples were a subset from the NEIGHBOR GWAS, all with high pressure primary open angle glaucoma (POAG). DNA was sequenced on Illumina instruments, generating at least 10 gigabases of data per sample. Reads were mapped to the hg19 reference human genome and single nucleotide polymorphisms (SNPs) identified using methods published in the literature with parameters optimized to minimize false positives. Allele and zygosity frequencies were calculated from genotype calls. Comparisons between cases and available general population databases were based on the less frequent (minor) allele in 1000G for every SNP site identified in at least 30 patients. For annotation, lists were constructed with genes reported as involved in glaucoma, retinal disease and other neurodegenerative diseases or with enriched expression in optic tissue.

Results: Clinical considerations allowed definition of constraints to apply to the SNP sites including the following: (a) A genomic aberration is not likely to be important as a primary cause if it occurs with frequency close to that in a general population; so a site was excluded unless its frequency in the cases was at least 0.20 higher than in every comparison database. (b) If a high frequency anomaly were causing disease, it would be more prevalent in the general population; so, although there is a possibility of lack of penetrance, sites with allele frequency >0.25 in any general population were excluded. Fisher's exact test with correction for multiple testing was used to assign p-values to resulting sites. This yielded 165 variants in 99 genes with significant p-values.

Conclusions: This search used SNPs found in codon, UTR, intron, and promoter regions, and revealed potentially causative genes related to this genetically complex, chronic eye disease. Genome variations with markedly higher occurrence in high pressure POAG patients than in the general population implicated 99 genes of the approximately 25,000 genes encoded in the human genome. This study supplements recent advances in understanding of POAG based on gene implication from GWAS and GWAS-related pathway analyses.

Keywords: 539 genetics • 629 optic nerve • 660 proteins encoded by disease genes  
×
×

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.

×