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Eranga Nishanthie Vithana, Monisha E Nongpiur, Zheng Li, Shamira A Perera, Rahat Husain, Tina Wong, Ching-Lin Ho, Ching-Yu Cheng, Tien Yin Wong, Chiea Chuen Khor, Tin Aung; Rare non-synonymous genetic variants do not account for susceptibility to primary angle closure glaucoma at eight known common variant GWAS loci.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5143.
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© ARVO (1962-2015); The Authors (2016-present)
Primary angle closure glaucoma (PACG) is an important cause of irreversible blindness in Asia. To date, a succession of two genome-wide association studies have uncovered strong (P<5x10-8) association at eight distinct gene loci, which affect the individual risk of PACG. As the eight loci are underlined by common genetic variants of modest effect size, we next investigated whether rarer mutations of higher penetrance exist within these loci. The observation of these rarer mutations would provide additional insight into the genetic architecture and disease biology of PACG.
We performed whole exome sequencing in 1,000 PACG cases and 1,000 controls of Singaporean Chinese descent. Coding exonic regions throughout the entire human genome was captured using the Roche Nimblegen SeqCap in-solution capture kit, and sequenced on the Illumina Hi-Seq 4000 platform. We considered samples with exome targeted read coverage was >20X over >80% of the exome target. Read-mapping and variant-calling were performed using very well described bioinformatics algorithms (e.g. BWA, GATK, and the unified genotyper tool from GATK). We specifically analyzed all non-synonymous rare variants with a minor allele frequency of <1% at the following known PACG common-variant GWAS loci (PLEKHA7, COL11A1, PCMTD1 – ST18, EPDR1, GLIS3, FERMT2, DPM2 – FAM102A, and CHAT). Both single variant and gene-based burden of mutational load was performed.
We tested a total of 591 rare, non-synonymous variants across 26 genes underlying the 8 previously reported genome-wide significant loci. We did not observe even nominal significance (P>0.05 for all comparisons) either with single variant or gene-based burden at all eight previously described GWAS loci underlined by common variants. Although non-synonymous variants within PSMC6 gene at the FERMT2 locus had a burden P = 0.011, this did not survive correction for multiple-testing.
Rare mutations of higher penetrance do not appear to be responsible for the associations seen with common, non-coding GWAS variants in the context of PACG. This suggests that causal variants for PACG may reside in non-coding regions with functional consequences on nearby genes. We next aim to complete sequencing a total of 2000 cases and 2000 controls for the results to be definitive.
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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