NEW YORK (GenomeWeb) – A genome-wide association study has highlighted dozens of new and known loci with apparent ties to intraocular pressure (IOP), a risk factor for the development and progression of glaucoma.
Through a GWAS involving nearly 69,800 individuals of European, Latino, Asian, or African ancestry with IOP measurements in their electronic health records, researchers from Kaiser Permanente Northern California and the University of California, San Francisco confirmed associations for seven loci already implicated in IOP and narrowed in on suspicious variants at 40 new loci. The latter set included 14 loci with genome-wide significant associations to IOP in a replication analysis that involved more than 37,900 additional participants of European or Asian ancestry.
As reported today in Nature Communications, the team found that the IOP-associated loci showed some overlap with those implicated in other eye conditions such as glaucoma, while expression data supported the notion that at least some of the newly-identified loci may contribute to eye pressure-related drainage of fluid from the eye.
"Our findings extend previous studies showing the important role for specific components of the [aqueous humor] drainage structure in controlling IOP," senior author Eric Jorgenson, a researcher at Kaiser Permanente Northern California, and his co-authors wrote.
It's known that IOP is influenced by the balance between production of watery liquid called aqueous humor in the eye and the drainage of this fluid, the authors explained, with IOP rising as drainage is reduced. It has been established that a jump in IOP can contribute to the neurodegeneration and vision loss associated with glaucoma, but they noted that "mechanisms controlling aqueous humor dynamics and IOP regulation are still poorly understood."
Using SNPs that were imputed and directly genotyped using Affymetrix arrays for 69,756 individuals from the "Genetic Epidemiology Research in Adult Health and Aging" cohort, the researchers searched for variants coinciding with 356,987 available IOP measurements, focusing on each individual's mean IOP across both eyes. The study participants were untreated, they noted, though 2,338 individuals had clinical diagnoses of primary open-angle glaucoma.
From the seven known and 40 new loci with potential ties to IOP in the discovery cohort, the team selected lead SNPs at the new loci for validation testing in another 37,930 European or Asian individuals. While 39 of the loci had the same directionality in the replication cohort, 14 remained genome-wide significant in that analysis.
An analysis involving the 2,338 individuals with glaucoma and 58,172 unaffected controls suggested that at least 42 of the 47 IOP-associated loci had potential associations with the same directionality in glaucoma — a set that included variants in genes such as TMCO1 or AFAP1 that were implicated in primary open-angle glaucoma in the past. The IOP GWAS also highlighted variants at loci already implicated in other eye conditions or traits, including central corneal thickness.
By folding in ocular tissue expression information for genes coinciding with the IOP-linked loci from the Ocular Tissue Database and the EyeSAGE database, the team saw signs that the variants identified fall in and around genes with particularly pronounced expression in optic nerve head tissue and tissue from the trabecular meshwork, which is part of the aqueous humor drainage machinery.
The study's authors noted that additional candidate genes contained variants with more tenuous ties to IOP in the GWAS, including genes in cellular signaling pathways and pathways related to extracellular matrix formation, endothelial cell functions, and other processes.
"The current study also highlights potential strong candidate genes for further investigation among the novel IOP loci identified, which replicated in the external sample, with substantial biological evidence from the literature and our in silico results," Jorgenson and co-authors wrote.