Genome wide association study in the Australian and New Zealand registry of advanced glaucoma identifies common sequence variants in ABCA1, AFAP1 and GMDS which confer risk of primary open-angle glaucoma, and replicate in multiple independent cohorts

Jamie Craig, Kathryn Burdon, Puya Gharahkhani, Alex Hewitt, David Mackey, Paul Mitchell, Stuart Graham, Ivan Goldberg, Andrew White, Janey Wiggs, Lou Pasquale, John Landers, Robert Casson, Jon Ruddle, Shiwani Sharma, Matthew Brown, Tiger Zhou, Emmanuelle Souzeau, Richard Mills, Stuart Macgregor

Research output: Contribution to journalMeeting abstract


Purpose: Primary open-angle glaucoma (POAG) is a major cause of blindness worldwide, and is strongly genetically determined. We aimed to define further genetic loci contributing to POAG in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG).

Methods: We performed a discovery genome-wide association study, using 1155 advanced POAG cases from ANZRAG and 1992 controls. Association of top associated SNPs were further investigated in two Australian replication cohorts (total 932 cases, 6862 controls), and two US replication cohorts (total 2616 cases, 2634 controls).

Results: Meta-analysis of all cohorts revealed three novel POAG loci reaching genome-wide significance. These loci are located upstream of ABCA1 (rs2472493 [G] OR = 1.31, P = 2.1 × 10−19), within AFAP1 (rs4619890 [G] OR = 1.20, P = 7.0 × 10−10), and within GMDS (rs11969985 [G] OR = 1.31, P = 7.7 × 10−10). Using RT-PCR, we showed all three genomewide significant associated genes are expressed within both human retina and other ocular tissues. For ABCA1 and AFAP1, using immunolabelling we demonstrated protein distribution in the eye consistent with the expression findings.

Conclusions: ABCA1 is a membrane-bound receptor involved in phospholipid efflux which regulates neuroinflammation and neurodegeneration in mouse brain and may influence glaucoma pathogenesis through similar function in the retina. AFAP1 encodes a protein binding to actin filaments enabling their crosslinking. Actin cytoskeleton-modulating signals are involved in regulating aqueous outflow and intraocular pressure.

These three new loci, in addition to our previously identified genes will help improve risk profiling for glaucoma improving management of high-risk individuals, and identify new therapeutic target pathways.
Original languageEnglish
Pages (from-to)27-28
Number of pages2
JournalClinical and Experimental Ophthalmology
Issue numberS1
Publication statusPublished - Nov 2014
EventThe Royal Australian and New Zealand College of Ophthalmologists, 46th Annual Scientific Congress - Brisbane, Australia
Duration: 22 Nov 201426 Nov 2014

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