A Genetic Epidemiologic Study of Candidate Genes Involved in the Optic Nerve Head Morphology

PURPOSE. The size of the optic nerve head, referred to as disc area (DA), and the vertical cup-disc ratio (VCDR), are clinically relevant parameters for glaucomatous optic neuropathy. Although these measures have a high heritability, little is known about the underlying genes. Previously, the genes SALL1 and SIX1 were found to be genome-wide significantly associated with DA and VCDR. The purpose of the present study was to investigate whether genes encoding protein known to interact with protein encoded by SALL1 and SIX1 are also associated with either DA or VCDR. METHODS. A total of 38 candidate genes were chosen covering all known proteins interacting with SALL1 and SIX1. These were initially studied in the Rotterdam Study (RS)-I, including 5312 Caucasian subjects characterized for DA and VCDR. Positive findings were further investigated in two independent cohorts (RS-II and RS-III) and finally replicated in a fourth population (ERF). Bonferroni correction was applied to the meta-analyses. RESULTS. Three loci were found to be associated with DA. The only locus significant after correcting for multiple testing is located on chromosome 11p13. Three single nucleotide polymorphisms (SNPs) in ELP4, a gene which neighbors and plays a crucial role in the expression of PAX6, show association in meta-analysis of the four cohorts yielding P values of respectively 4.79 x 10(-6), 3.92 x 10(-6), and 4.88 x 10-6 which is below the threshold dictated by the most conservative Bonferroni correction (P = 5.2 x 10(-6)). CONCLUSIONS. This study suggests that the ELP4-PAX6 region plays a role in the DA. Further research to confirm this finding is needed. (Invest Ophthalmol Vis Sci. 2012;53:1485-1491) DOI:10.1167/iovs.11-738

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma

The vast complexity of primary open angle glaucoma:Disease genes, risks, molecular mechanisms and pathobiology

<p>Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG.</p><p>Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPEN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer's disease. (C) 2013 Elsevier Ltd. All rights reserved.</p>