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Shi Song Rong, Robert Igo, Jessica Cooke Bailey, Jonathan L Haines, Louis Pasquale, Janey Wiggs; Analysis of ATXN2 trinucleotide repeats in primary open angle glaucoma patients. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1247.
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Genome-wide association studies (GWAS) have identified significant association of ATXN2 with primary open angle glaucoma (POAG) and intraocular pressure. ATXN2 includes a polyglutamine (CAG) repeat that when fully expanded (>34 repeats) causes spinocerebellar ataxia 2. Intermediate-length expansions (27-33 repeats) have been reported as a risk factor for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, suggesting that the CAG repeat expansions could also contribute to POAG risk. The purpose of this study is to evaluate the frequencies of ATXN2 CAG repeat alleles in POAG cases and controls.
The genomic region that includes ATXN2 (hg19 chr12:111,833,387-112,075,976) was sequenced in 221 POAG cases using Haloplex capture followed by alignment and base calling using the GATK pipeline. The CAG repeat sequences were identified by manual inspection of the aligned reads from the Haloplex sequencing with a mean depth of 315. Fragment analysis was used to size the repeat alleles in cases as well as controls (N=213). Sanger sequencing was done in controls with the expanded repeats. Single nucleotide polymorphisms (SNPs) spanning ATXN2 were called from Haloplex sequence data of >200 depth. SNPs in linkage disequilibrium (LD) with CAG repeat alleles were tested for association with POAG in GWAS data from the NEIGHBORHOOD consortium (3,853 cases and 33,480 controls).
In POAG cases, 18 different CAG repeat alleles were identified ranging from 19 to 27 repeats with a mean repeat count of 22. In controls, the CAG repeat alleles ranged from 17 to 27 repeats and also had a mean repeat count of 22. The largest repeat allele (27 repeats) was an interrupted CAG repeat, (CAG)8(CAA)(CAG)4(CAA)(CAG)4(CAA)(CAG)8, found in 9 cases and in 6 controls. To determine if the 27-repeat allele is associated with POAG, a proxy SNP (rs117129118) in complete LD (r2=1) with the 27 repeat allele was identified from the Haloplex sequence data. We extracted the association results from the NEIGHBORHOOD consortium for rs117129118 in POAG, high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). The results suggested that rs117129118 was not associated with POAG (OR=0.9, P=0.65), HTG (OR=0.9, P=0.71), or NTG (OR=0.7, P=0.28).
These results suggest that expansion of the ATXN2 polyglutamine repeat associated with ALS and other neurodegenerative diseases does not contribute to POAG risk.
This is a 2020 ARVO Annual Meeting abstract.
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