Discovery of novel loci for primary open angle glaucoma using combined extreme extreme phenotype and QTL approaches.

Abstract

Purpose : To use an enlarged cohort of POAG cases with advanced disease to discover novel susceptibility loci for glaucoma development.

Methods : We performed a meta-analysis of Australian genome-wide association studies (GWAS) for POAG, with GWAS data for IOP, and the optic disc parameters. Genome-wide association studies were performed separately for a total of 3,071 POAG cases from the Australian & New Zealand Registry of Advanced Glaucoma and 6,750 unscreened controls. GWAS summary results were then meta-analysed with publicly available GWAS data for IOP and optic disc parameters such as VCDR on ~24000 individuals of European ancestry.

Results : Using this approach, in addition to the previously identified glaucoma loci, we identified four novel risk loci including regions on 6p21.31, 20q13.12, 3q27.3, and 9q33.3 in the meta-analysis. We then used gene-based and pathway-based approaches to identify further genes and relevant cellular mechanisms involved in POAG. Eight further novel risk loci were identified using gene-based approaches, amongst which two loci have previously showed associations with age-related macular degeneration, refractive error, axial length, and myopia, suggesting an overlap of the genetic risk factors between these eye diseases.

Conclusions : The novel risk loci in addition to the previously known risk loci will improve risk profiling for glaucoma, providing better opportunities to identify high-risk individuals. The data generated using discovery sets biased to severe disease is particularly relevant to the prediction of poor outcome in glaucoma. Fine-mapping and functional studies of new risk loci will improve understanding of the pathogenesis of glaucoma, facilitating development of new therapeutic strategies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.