Genome-wide multi-ethnic meta-analysis identifies 22 independent risk loci for normal tension glaucoma and predominantly overlaps with high tension glaucoma.

Abstract

Background Primary open-angle glaucoma (POAG) is often divided into two subtypes. High-tension glaucoma (HTG) is characterized by elevated intraocular pressure (IOP), while normal-tension glaucoma (NTG) is characterized by IOP consistently in the normal range. However, this notion is still controversial as some studies argue that different tension subtypes is part of the same pathogenic process while other studies claim that NTG represents a different etiological process where primary neurodegeneration has a higher impact. This study aimed to elucidate the shared and distinct genetic architecture for NTG and HTG. Method To identify risk loci specific to NTG, we conducted a large international multi-ethnic multi-trait meta-analysis of 7,942 NTG cases and 384,431 controls without any form of glaucoma, and a structural measurement of the integrity of the optic nerve, vertical cup-to-disc ratio (VCDR, N = 282,100), adjusted for IOP using the mtCOJO method. We also performed an assessment of the genetic overlap between NTG and HTG (N HTG cases = 5144, N controls = 47,997) using the GWAS pairwise method (GWAS-PW). Findings: This study identified 22 risk loci associated with NTG. Of these, 17 loci are novel for NTG, and two loci, BMP4 and TBKBP1, have not previously been associated at the genome-wide significant level with glaucoma. The contribution of BMP4 in the development of NTG was further supported by integrating single-cell transcriptomic data from neuron-like cells, along with methylomic data from peripheral blood. Examination of each locus across the genome using the GWAS-PW method indicated that risk loci are shared across NTG and HTG. The magnitude of the effect of the genome-wide significant loci tends to be lower in NTG compared to their effects on HTG, particularly for IOP-related loci. Additionally, we identified 42 drug-gene interactions with four genes (ABCA1, CDKN2A, CDKN2B and ITGB3) that were prioritized through our gene-based analysis. Interpretation: This work expands our understanding of the genetics of NTG and highlights a strong genetic overlap between HTG and NTG. Despite the genetic overlap, we have shown that IOP-related loci tend to have a smaller effect size in NTG when compared with HTG whereas neurodegenerative loci independent of IOP have similar effect sizes on NTG and HTG. These results indicate that while there is a significant overlap in risk loci between NTG and HTG, a precise estimation of their effect sizes on NTG using larger studies could help develop genetic risk prediction models to identify individuals at a higher risk of developing NTG. We have also identified some potential targets for neuroprotective treatment through the interaction of four genes and multiple drugs. By harnessing multi-omics data, we substantiated the involvement of gene expression and DNA methylation of BMP4 in the etiology of NTG.