Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

“…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 or IOP). For POAG, summary statistics were taken from the International Glaucoma Genetics Consortium (IGGC) meta-analysis [ 24 ], and for IOP, summary statistics taken from [ 26 ]. As expected, there was evidence for a strong causal link between IOP and POAG, with strong concordance of the effects of variants on IOP with the effects on POAG ( Fig 6A and 6B ).…”

“…(D) Forest plot showing effect size and direction of SNPs significantly associated with the thickness of the GCIPL on POAG. POAG summary statistics were taken from the POAG International Glaucoma Genetics Consortium (IGGC) meta-analysis [ 24 ]. Summary statistics for genetic association studies of IOP, were taken from [ 26 ].…”

“…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 showing effect size and direction of SNPs significantly associated with the thickness of the GCIPL on POAG. POAG summary statistics were taken from the POAG International Glaucoma Genetics Consortium (IGGC) meta-analysis [24]. Summary statistics for genetic association studies of IOP, were taken from [26].…”

“…The thickness of the Ganglion Cell Complex (GCC), the collective name for the RNFL and GCIPL, is one of the biomarkers used in diagnosis of primary open angle glaucoma (POAG) [19,20]. Studies have found genetic variants associated with glaucoma [21][22][23][24], as well as other endophenotypes of the disease such as intraocular pressure (IOP), one of the major risk factors for glaucoma [25,26]. A number of well-defined loci are known to affect POAG, with over 100 loci reportedly associated with the disease, including at CDKN2B-AS1, SIX1/SIX6, CAV1/CAV2, TMCO1 and GAS7 amongst others [22,24,27].…”

“…Studies have found genetic variants associated with glaucoma [21][22][23][24], as well as other endophenotypes of the disease such as intraocular pressure (IOP), one of the major risk factors for glaucoma [25,26]. A number of well-defined loci are known to affect POAG, with over 100 loci reportedly associated with the disease, including at CDKN2B-AS1, SIX1/SIX6, CAV1/CAV2, TMCO1 and GAS7 amongst others [22,24,27]. Genetic influence on retinal morphology has been previously studied [28] but largely in smaller cohorts or focused on looking at the retina as a whole [29].…”