Oral Presentation 9th GeneMappers Conference 2012

Dissection of Genetic Risk Factors for Primary Open Angle Glaucoma in a Cohort of Patients with Advanced Glaucoma (#3)

Jamie E Craig 1 , Kathryn P Burdon 1 , Rhys Fogarty 1 , David A Mackey 2 , Matthew A Brown 3 , Paul Leo 3 , Alex W Hewitt 4 , Paul Mitchell 5 , Australian and New Zealand Registry of Advanced Glaucoma
  1. Flinders University, Adelaide, SA, Australia
  2. Lions Eye Institute, University of Western Australia, Perth, Australia
  3. Diamantina Institute, Brisbane, Australia
  4. Lions Eye Institute, University of Western Australia, Perth, Australia
  5. Ophthalmolgoy, University of Sydney, Save Sight Institute, Sydney, Australia

Primary Open Angle Glaucoma (POAG) is a leading causes of blindness worldwide. Vision loss can be prevented or delayed by timely treatment, but in some patients disease continues to progress. Recently, our GWAS of 590 patients with an extreme glaucoma phenotype (Advanced Glaucoma) identified association at TMCO1 and CDKN2B-AS1 while other studies have identified CAV1/CAV2 and SIX1/SIX6. To identify additional loci for POAG, we have doubled the size of our first study.
Advanced Glaucoma was defined as severe central visual field loss due to POAG. In total, 1090 patients were genotyped on either the OmniQuad (phase 1) or OmniExpress (phase 2) SNP array (Illumina). Genotype data were merged with historic control data from the WTCCC 1958 Birth Cohort, the Illumina iControl database and the Blue Mountains Eye Study typed on Illumina HumanHap arrays (n=7173). There were 164,984 SNPs common to all datasets. Principal Components were calcuated in Eigensoft and outliers removed. Association analysis was conducted in Plink, adjusting for principal components. Data was imputed to HapMap2 with Mach. Cases were also analysed stratified for peak intraocular pressure >21 mmHg (High Tension Glaucoma, n=691) or ≤21 mmHg (Normal Tension Glaucoma, n=323).

Analysis of the genotyped SNPs confirmed association at TMCO1 and CDKN2B-AS1. Three novel loci were identified at genome-wide significance: chromosome 4, p=2.2x10-13; chromosome 1, p=7.5x10-13; and a second locus on chromosome 4, p=1.8x10-8. The imputed data supported these findings but did not identify any additional loci or SNPs with more significant p-values. These 3 loci are undergoing independent replication studies. Stratification of the data by intraocular pressure showed that the CDKN2B-AS1 locus is more significantly associated with Normal Tension Glaucoma while the TMCO1 locus and the two newly identified chromosome 4 regions are more strongly associated in the High Tension sample.

This GWAS for Advanced Glaucoma has identified 5 POAG associated loci at genome-wide significance and is a valuable resource for the further dissection of the complex POAG phenotype.