A multi-ethnic genome-wide association study of primary-open angle glaucoma identifies novel risk loci

Abstract

Purpose : Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness. Genome-wide association studies (GWAS) have reported a number of loci associated with primary-open angle glaucoma (POAG), the most common type of glaucoma, often associated with elevated intraocular pressure (IOP). However, these loci explain little heritability, suggesting many remain undiscovered.

Methods : We conducted a GWAS of POAG in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, consisting of 4,986 POAG cases and 58,426 controls from four race/ethnicity groups (non-Hispanic whites, Hispanic/Latinos, East Asians, and African-Americans). We tested novel loci discovered in GERA in an external replication cohort: the multi-ethnic UK Biobank (UKB), which includes 7,329 glaucoma cases and 169,561 controls. We then conversely investigated novel glaucoma-associated loci from the UKB in GERA, and conducted a multi-ethnic meta-analysis combining GERA and UKB. Finally, expression of the genes at the identified loci was assessed in silico in human ocular tissues using publicly available databases.

Results : We identified 12 loci associated with POAG at genome-wide significance (P<5.0x10^-8) in the GERA discovery cohort, of which 5 were novel. Three novel loci (FMNL2, PDE7B, and TMTC2) replicated at Bonferroni significance in UKB with the same direction of effect. The GWAS of glaucoma in the UKB identified 9 additional novel loci, 6 of which replicated in GERA (IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). A meta-analysis combining GERA and UKB identified 24 additional novel loci that would still require external replication. Most of the genes at the identified loci were expressed in ocular tissues with relevance in glaucoma pathogenesis. Interestingly, variants at FMNL2 and DGKG have also been shown to be associated with higher IOP levels in our recent GWAS of IOP.

Conclusions : Our findings provide evidence that some, but not all genes, likely contribute to glaucoma risk through their effect on elevated IOP. Identification of novel loci underlying POAG/glaucoma represents an important step toward understanding glaucoma genetic etiology.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.