An International Genome-Wide Association Study of Glaucoma-Related Optic Disc Parameters in 18,000 Caucasians: the International Glaucoma Genetics Consortium

Abstract

Purpose: Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. There has been rapid progress in identifying genes involved in glaucoma or related optic nerve pathology. The goal of this study was to identify new genes associated with optic disc parameters.

Methods: We conducted an international meta-analysis of genome-wide association studies (GWAS) testing 2.5 million single nucleotide polymorphisms in ± 18,000 Caucasians from 9 different cohorts within the International Glaucoma Genetics Consortium. The outcomes were adjusted for age and sex and included vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA) and rim area (RA).

Results: New genome-wide significant loci (p<5x10^-8) were identified on chromosome (chr.) 1 (DA and RA), 3 (VCDR and CA), 6 (VCDR and CA [different loci]), 10 (VCDR and CA), 11 (VCDR and CA), 17 (RA) and 20 (VCDR). These new loci are located in or near genes with different functions. There were 3 genes involved in the pathogenesis of breast cancer (on chr. 6, 17 and CHEK2 [see later]). The gene on chr. 1 may play a role in peripheral actin formation and the promoting of cytoskeletal reorganization. COL8A1 (chr.3) is part of a collagen pathway recently implicated in an in press GWAS meta-analysis of corneal thickness and a component of the Descemet’s membrane. The gene on chr. 6 (VCDR) is essential for the targeting of vesicles to the plasma membrane. The other region on chr. 6 (CA) contains, beside 2 genes which may play a role in breast cancer cells, one gene involved in central nervous system defects. The gene on chr. 10 plays a role in various processes: cell growth, differentiation and gene expression. The chr. 11 gene has been associated with patients with scleroderma and/or Sjogren’s syndrome. It is suggested that the gene on chr. 20 may play a role in promoting and maintaining of ganglion cell growth. We also found several genome-wide significant loci in or near genes, which were previously published (CDC7/TGFB3, CDKN2B, ATOH7, TMTC2, SIX1, SALL1, CHEK2).

Conclusions: Our meta-analysis revealed several new loci associated with one or more optic disc endophenotypes of glaucoma. The functions of these new genes vary from regulation of corneal thickness to (ganglion) cell growth. The data highlight the complex etiology of optic nerve changes in glaucoma.

Keywords: 627 optic disc • 539 genetics