June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
A whole exome sequencing survey of primary angle closure glaucoma
Author Affiliations & Notes
  • Tin Aung
    Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Medical School, Singapore, Singapore
  • Footnotes
    Commercial Relationships   Tin Aung None
  • Footnotes
    Support  National Medical Research Council, Singapore
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4355. doi:
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      Tin Aung; A whole exome sequencing survey of primary angle closure glaucoma. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4355.

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

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Purpose : Primary angle closure glaucoma (PACG) is a major form of glaucoma worldwide. To date, two genome-wide association studies (GWAS) on >20,000 participants have revealed eight genetic loci that are significantly and reproducibly associated with PACG risk. However, the relative risk attributable to all eight loci was modest. By building on the previous two GWAS, the purpose of this study was to evaluate the genome-wide contribution of protein-altering genetic variants to PACG risk.

Methods : A total of 4,693 PACG cases and 5,508 controls from Singapore, Japan, Hong Kong, and Vietnam underwent whole-exome sequencing libraries using the 2x150 paired end chemistry on the Illumina Novaseq6000 sequencer. Standard bioinformatics pipelines for sequencing data clean up, sequence read alignment, and identification of genetic variants were then performed on all samples blinded to affection status. After stringent quality control checks to remove samples and genetic variants with low completion rates, as well as outliers on quality metrices such as read depth, allelic balance, outlying genetic ancestry, and samples showing evidence of cross-contamination, the remaining samples were subjected to gene-based burden tests. The gene-based burden test aggregates all rare, protein altering genetic variants within each gene and evaluates for overrepresentation of these rare variants in PACG cases compared to controls. Experiment-wide significance was set at P=0.05/20,000 genes =2.5×10-6.

Results : Contrary to other eye diseases such as age-related macular degeneration, we did not observe significant associations between rare variant burden at all eight previously implicated PACG GWAS loci (PLEKHA7, COL11A1, PCMTD1ST18, EPDR1, CHAT, GLIS3, DPM2FAM102A, and FERMT2; P>0.2 for all comparisons). In addition, we did not observe significant association for all genes located within a 1Mb interval in the vicinity of all eight loci (P>0.2 for all comparisons). A broader, exome-wide evaluation revealed a provisionally significant finding of rare, protein-altering genetic variants at chromosome 20p13 (P=1.1 ×10-6) with large effect size.

Conclusions : The coding genetic architecture for primary angle closure glaucoma was observed to be significantly different from the genetic landscape as revealed by common-variant GWAS. We are attempting to replicate the fidning at Chr 20p13 in additional independently ascertained PACG collections.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.


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