A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

Abstract

We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer's disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide 1,2 . The disease is characterized by progressive optic nerve degeneration that is usually accompanied by elevated intraocular pressure (IOP). Neuroprotective therapies are not available and current treatments are limited to lowering IOP which can slow disease progression at early disease stages. However over 50% of glaucoma is not diagnosed until irreversible optic nerve damage has occurred 2,3 .

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank Optical Coherence Tomography images

“…As expected, a Mendelian randomisation test in the reverse direction did provide some weak rs13076750 rs1381486 rs56299331 rs2526385 rs10852918 rs61755579 rs2022945 rs5754187 rs2279499 rs62520914 rs3088214 rs9608740 rs10898526 rs10189434 rs3778519 rs6065171 rs12350252 rs9912530 rs4775427 rs17534001 rs12139208 rs9913911 rs4074961 rs1874458 rs9364973 rs368503 rs1579050 rs79449167 rs11217863 rs7924522 rs676015 rs1286771 rs10918274 rs2745572 rs4714896 rs9504807 rs2214230 rs11038409 rs2526099 rs12879626 rs2472494 rs67889059 rs2292737 rs62283814 rs7338461 associated with the thickness of the GCIPL on POAG. POAG summary statistics were taken from the POAG International Glaucoma Genetics Consortium (IGGC) meta analysis [43]. Summary statistics for genetic association studies of IOP, were taken from [24].…”

“…Prompted by the surprising lack of overlap between the inner retinal phenotypes and the established inner retinal disease of glaucoma, we performed two-sample Mendelian randomisation studies between the retinal morphology traits (RNFL and GCIPL), IOP and POAG. Mendelian randomisation is a statistical technique that uses genetics to test a suspected causal relationship between an "exposure" variable (in this case IOP, RNFL or GCIPL thickness) and an outcome variable (in this case POAG, with summary statistics taken from the International Glaucoma Genetics Consortium (IGGC) meta-analysis [43], or IOP, with summary statistics taken from [24]). As expected, there was evidence for a strong causal link between IOP and Conducting the analysis with POAG or IOP as the exposure, and retinal thickness as the outcome, there was no evidence for an effect of IOP on retinal layer thickness, and at most weak support via one meta-analysis technique for a causal relationship between POAG and retinal thickness of both GCIPL and RNFL (Supplementary Figure 12 & 13, Supplementary Table 8); given the strong causal link of IOP to POAG shown by both MR and drug treatments, if this causal link between POAG and inner retinal thickness is present, this data indicates that it is not on the causal pathway with IOP, and likely takes a different biological route.…”

“…The internal LD pruning function was also applied to all exposure variables. POAG summary statistics were used from the POAG International Glaucoma Genetics Consortium (IGGC) meta analysis [43]. The GCIPL and RNFL thickness (whether used as an exposure or an outcome) had the same set of technical covariates applied as the GWAS listed above.…”

“…F) Forest plot showing the effect size and direction of SNPs significantly associated with POAG on the meta analysed GCIPL and RNFL thickness. POAG summary statistics were taken from the POAG International Glaucoma Genetics Consortium (IGGC) meta analysis [43].…”

“…Association of UK Biobank inner retinal thickness-associated variants with primary open-angle glaucoma in the International Glaucoma Genetics Consortium meta-analysis[43] Betas and p-values for models of SNP effect on total retinal thickness at the fovea and visual acuity. LogMAR letters beta refers to the difference in number of letters read on a standard LogMAR chart.…”