POAG is a genetically and phenotypically complex disease. Genetic factors—through interactions with other genes, environmental factors, or both—may influence both IOP and optic nerve susceptibility. One approach to identify genes that predispose to complex traits such as POAG is to define phenotypic subtypes or endophenotypes that are phenotypically homogeneous and may be caused by a smaller set of susceptibility genes. Ocular quantitative traits are a type of endophenotype that have the added advantages of precise measurement and continuous trait analysis, features that enhance gene discovery by minimizing misclassification and increasing study power.
In this study, we have shown that SNPs located in two VCDR quantitative trait loci on 9p22 and 14q22–23 (rs1063192 and rs10483727, respectively) are also associated with POAG in a US Caucasian population. The T allele of rs10483727, located near the SIX1/SIX6 gene complex on chromosome 14q22–23, is associated with a larger VCDR and an increased risk for POAG, whereas the G allele of rs1063192, located within the CDNKN2B gene on chromosome 9p22, is associated with a smaller VCDR and a decreased risk for POAG. Collectively, these results suggest that genetic variants influencing normal variation in VCDR are risk factors for the progressive increase in VCDR found in persons with POAG.
SNP rs1900004, located near the ATOH7
gene, is a major factor controlling optic nerve area.15,16
Although this SNP was not independently associated with POAG, we identified a significant interaction with SNP rs10483727 such that persons who carry the rs10483727 risk genotype TT or TC were more likely to develop POAG if they also carried the rs1900004 genotype associated with larger optic nerve area (CC). Previous studies have suggested that persons with larger disc areas are at increased risk for POAG and other forms of glaucoma.18
Our results suggest that optic disc area alone is not necessarily a risk factor for glaucoma but that it can significantly increase disease risk when coupled with risk factors controlling vertical cup-to-disc ratio.
gene codes for Math5, a protein known to regulate retinal ganglion cell histogenesis in vertebrate model organisms,19
and recent analyses from both the Rotterdam study15
and the Australian group16
indicate that this gene is a major factor controlling optic disc area. The gene products of both the SIX1
genes are also developmentally regulated transcription factors.20–22
Mutations in SIX1
are a cause of the brachio-oto-renal syndrome,22
whereas mutations in SIX6
have been shown to cause anophthalmia.21
Our results showing that rs10483727 is associated with POAG as well as VCDR suggest that one or both of the SIX1/SIX6
genes may also contribute to optic nerve or retinal ganglion cell development. In addition, the interactive effect with rs1900004 could suggest that the SIX1/SIX6
gene complex may participate in developmental pathways that include ATOH7
SNP rs1063192 is located on chromosome 9p21 within the CDKN2B
gene and adjacent to CDKN2A
, a tumor suppressor gene. The CDKN2B protein is a cyclin-dependent kinase that may regulate cell growth and is induced by transforming growth factor beta (TGF-β). TGF-β is a multifunctional cytokine that modulates developmental and repair processes in several tissues, including the retina and trabecular meshwork.23,24
gene has also been associated with type 2 diabetes mellitus (T2DM) in several genomewide association studies.25–27
T2DM has been implicated as a risk factor for POAG,28
suggesting that further investigation among CDKN2B
, POAG, T2DM, and glycemic load could be of interest. In this study, we confirm that the G allele is associated with a smaller VCDR and also show that carriers of the G allele are less likely to develop POAG. Collectively, these results add further support for a role of TGF-β in glaucoma and suggest that other proteins in the TGF-β signaling pathways may also contribute to glaucoma pathogenesis.
The SNPs associated with POAG and optic nerve parameters are all connected with genes that can influence optic nerve quantitative parameters through developmental processes. Although genes regulating ocular development may not be obvious candidates as risk modulators for a progressive late-onset disease such as POAG, our results suggest that such genes may, in fact, be one set of risk factors predisposing to POAG. Further study will be needed to determine whether these genetic risk factors participate in optic nerve and ganglion cell repair or have other metabolic roles in addition to regulating optic nerve size and structure.
Our study provides confirmation that a quantitative trait-mapping approach can be used to identify genetic risk factors for a genetically and phenotypically complex disease such as POAG. The identification of additional genetic factors influencing other ocular quantitative traits that could contribute to POAG will help further define the genetic architecture of this important blinding disease.