Meta‐analysis of Genome‐Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Abstract

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

“…6p25, and DGKB on chr. 7p21.2) (Supplementary Materials, Figs S7 and S8); the other genomic regions have been previously associated with VCDR or cup area, two highly correlated traits (19)(20)(21). Of the five novel genomic regions, RREB1 (P-value ¼ 4.13 Â 10 À3 ) was nominally significant in the analysis of individuals of Asian descent (n ¼ 8,373, k ¼ 1.01).…”

“…These genes were previously associated with the disc area, so the novel associations with VCDR could possibly be driven by the influence of the disc area on VCDR (21). In the cup area analysis, the genes LRP10 (P-value 1.20 Â 10 À6 ) and REM2 (P-value 1.55 Â 10 À6 ), and THSD4 (P-value 5.44 Â 10 8 ) were significantly associated.…”

“…The meta-analysis of individuals of European descent (n ¼ 22,489, k ¼ 1.06) yielded 17 genome-wide significant regions of which 14 regions were already implicated for cup area or VCDR (Supplementary Materials, Figs S9A, S10A and Table S5) (20,21). There were three novel associations on chr.…”

“…14q11.2 (Supplementary Materials, Figs S5B and S6B), were genome-wide significant leading to a total of nine (5 þ 4) novel genomic regions associated with VCDR. Of these novel genomic regions, F5 has been associated with the disc area previously (21). Disc area influences the VCDR (22), and therefore we corrected VCDR for disc area in a secondary analysis.…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…There are, however, several genetic variants within the collagen genes that are significantly associated with glaucomatous endophenotypes such as maximum vertical cup-disc ratio, increased optic disc cup area and altered central corneal thickness [29][30][31][32]. Other mutations within fibrillin 1, latent-transforming growth factor beta-binding protein 2 and versican genes have been associated with glaucoma in humans [33][34][35][36][37].…”