Abstract
Purpose :
Genome-wide association studies (GWAS) have identified significant association of SNPs located in the ATXN2 genomic region with primary open angle glaucoma (POAG) and intraocular pressure (IOP). The ATXN2 coding sequence includes a CAG repeat that when fully expanded (>34 repeats) causes spinocerebellar ataxia 2, and intermediate expansions (24-34 repeats) contribute to risk of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. In this study, we investigated this ATXN2 CAG repeat in POAG.
Methods :
Fragment analysis was used to size the CAG repeat in 229 POAG cases and 213 controls selected from the NEIGHBORHOOD cohort. The entire repeat genomic region was sequenced using Haloplex next-generation sequencing (NGS) for the 229 POAG cases and 30 controls. SNPs in high LD (linkage disequilibrium)(r2>0.95) with CAG repeats were used to test for association with POAG in the overall NEIGHBORHOOD case control cohort, and for association with POAG and related ocular traits in other published GWAS summary data.
Results :
The CAG repeat size ranged from 19 to 27 in POAG cases and from 17 to 27 in controls. Both groups had a mean repeat size of 22, which is the average repeat size in normal populations. Among the 19 different repeat sequences identified by NGS, the most common sequence >22 was a 27 repeat ((CAG)8(CAA)(CAG)4(CAA)(CAG)4(CAA)(CAG)8) with a frequency of 2% in both cases and controls. All other repeats >22 had frequencies of <0.2% in the sequenced individuals. A SNP in high LD (r2>0.95) with the 27 repeat (rs117129118) was not significantly associated with POAG (N=2606 cases, 2606 controls), or high-tension (N=1298) or low-tension glaucoma (N=561) in the NEIGHBORHOOD dataset (P>0.05). In published GWAS summary data, rs117129118 was also not associated with POAG, IOP, CDR, or CCT.
Conclusions :
Expansion of the ATXN2 CAG repeat was not associated with POAG in a large case/control cohort suggesting that expansion of the ATXN2 CAG repeat does not alter glaucoma risk. These results suggest that other genetic variants in the ATXN2 locus contribute to POAG risk.
This is a 2021 ARVO Annual Meeting abstract.