July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Preliminary Results of Whole exome sequencing of Primary Angle Closure Glaucoma in 1,000 Singaporean Chinese cases and 1,000 controls
Author Affiliations & Notes
  • Tin Aung
    Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, --------, Singapore
    National University of Singapore, Singapore, --------, Singapore
  • Eranga Vithana
    Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, --------, Singapore
  • Monisha E Nongpiur
    Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, --------, Singapore
  • Shamira Perera
    Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, --------, Singapore
  • Chiea Chuen Khor
    Genome Institute of Singapore, Singapore, --------, Singapore
  • Footnotes
    Commercial Relationships   Tin Aung, None; Eranga Vithana, None; Monisha Nongpiur, None; Shamira Perera, None; Chiea Chuen Khor, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5149. doi:
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    • Get Citation

      Tin Aung, Eranga Vithana, Monisha E Nongpiur, Shamira Perera, Chiea Chuen Khor; Preliminary Results of Whole exome sequencing of Primary Angle Closure Glaucoma in 1,000 Singaporean Chinese cases and 1,000 controls. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5149.

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

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Abstract

Purpose : To date, two genome-wide association studies have uncovered strong (P<5x10-8) association at eight distinct gene loci which affect individual risk of primary angle closure glaucoma (PACG). As the eight loci are underlined by common genetic variants of modest effect size, we next asked whether rarer mutations of higher penetrance exist within the coding frame.

Methods : We performed whole exome sequencing in 1,000 PACG cases and 1,000 controls of Singaporean Chinese descent, all of whom had previously undergone genome-wide genotyping. Controls were enrolled from a population-based study, and were confirmed to have open angles. The exonic protein coding regions of the entire genome was captured using the Roche Nimblegen SeqCap v3 solution-based hybridization method. All 1000 PACG cases and 1000 controls underwent whole-exome capture and thereafter sequenced together on the same Illumina Flow Cell. Samples were considered completed when >80% of the target bases have >20x coverage. After completion of sequencing, read mapping and variant calling were performed using well described bioinformatic algorithms (e.g. BWA, GATK, and the unified genotyper tool from GATK). Association analysis between non-synonymous, protein-changing genetic variants and PACG disease risk was performed for single variants as well as using a collapsing burden test for rare variants (defined as coding variants having a frequency of <1%) within each annotated gene.

Results : We observed reasonable coverage of exomic coding-region content, with median depth of coverage for PACG cases and controls at 57X. Further analysis revealed that on average for each sample, 95% of targeted exonic bases were covered 10X or more and 89% of targeted exonic basese were covered 20X or more. No single genetic variant achieved exome-wide significance. The collapsing gene-based burden test for mutational load of rare variants also did not reveal any genetic variant surpassing exome-wide significance (defined as P<5x10-7). We did not observe any single variant achieving exome-wide significance

Conclusions : Our preliminary effort in performing whole exome sequencing for 1000 PACG cases and 1000 controls did not reveal exome-wide significant findings. We are aiming to complete whole exome sequencing in a total of 2000 PACG cases and 2000 controls.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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