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Glaucoma Opinion IGR 13-3

Update on Glaucoma Genetics

Janey L. Wiggs

The discovery of genes predisposing to glaucoma is the first step toward the development of gene-based screening tests and novel therapies targeted to the molecular events that are responsible for the disease. Until recently, the search for glaucoma genes has been limited to genetic linkage studies that required large families affected by early-onset mendelian forms of disease, or atypical forms of adult-onset disease. Not surprisingly, these studies have not yielded genes that are major factors influencing glaucoma pathogenesis. However, recent advances in molecular genetics and genomics now make it possible to study the genetic etiologies of common forms of adult-onset glaucoma. In the particular, the annotation of the human genome sequence and the development of the HapMap1 have facilitated genome-wide association studies identifying genes contributing to ocular quantitative traits related to glaucoma pathogenesis (cup/disc ratio, CDR; optic nerve size and central corneal thickness, CCT), as well as genes associated with exfoliation syndrome and primary open-angle glaucoma.

Optic nerve parameters such as disc area and CDR are highly heritable and show substantial variation in human populations. Genome-wide analysis of ocular quantitative traits using large normal populations has lead to the identification of CDKN2BAS and SIX1SIX6 as genetic risk factors contributing to the CDR,2 and the ATOH7 gene as an important determinant of optic nerve size.3 Populations from around with world have been used to identify genetic factors contributing to CCT, one of the most heritable of the ocular quantitative traits.4-8 Interestingly, a number of the genes associated with CCT appear to be population specific, although several, including the ZNF469 and COL8A2 have been identified in ethnically diverse populations. Other ocular quantitative traits related to glaucoma remain to be studied including nerve fiber layer thickness and corneal hysteresis.

The GWAS (genome-wide association study) approach is also proving to be a successful method to identify genes contributing to common forms of adult glaucoma including exfoliation syndrome and primary open-angle glaucoma (POAG). Using information from the HapMap, genetic markers (SNPs) 'tagging' large blocks of genomic DNA sequence are selected for case control association analyses. Typically over 500,000 SNPs spanning the entire human genome are evaluated. This approach identified LOXL1 as a major genetic risk factor for exfoliation syndrome,9 a finding that has been replicated in populations world-wide (reviewed in reference 10). Recent studies suggest that LOXL1 gene variants may influence disease development by reducing LOXL1 gene expression.11-12 The frequency of LOXL1 risk alleles is high in both affected and unaffected individuals arguing that other factors, which could genetic or environmental, must also contribute to the disease.10

Several GWAS for POAG have been completed. A study from Iceland using 1,263 cases and over 34,877 controls identified DNA sequence variants in the CAV1/CAV2 gene region associated with POAG.13 This finding has been replicated in a study of Caucasian cases and controls from the US (GLAUGEN).14 Using 590 advanced glaucoma cases and 3,956 controls the CDKN2BAS (previously associated with CDR) and TMCO1 genes were found to be associated with POAG in a study of Australian cases and controls.15 The CDKN2BAS and SIX1/SIX6 genes were also associated with POAG in 3500 cases and controls analyzed in a meta-analysis of the GLAUGEN and NEIGHBOR studies.16 None of the current glaucoma genes account for a significant proportion of POAG in the general population suggesting that additional glaucoma genes await discovery.17 Biologically, the genes currently known to contribute to POAG are pointing to two molecular pathways that may influence glaucomatous optic nerve degeneration. In a recent study of genomic copy number variants (CNVs, including deletions, duplications and insertions) a duplication of the TBK1 gene was identified as a factor contributing to the development of normal-tension glaucoma in a large African American family.18 TBK1 interacts with optineurin, a protein that is also a rare cause of normal-tension glaucoma.19 Both TBK1 and optineurin participate in the TNF alpha signaling pathway20-21 suggesting that TNF alpha signaling can contribute to optic nerve disease in glaucoma and that other proteins in this pathway may also be associated with normal-tension glaucoma. Similarly, the association of CKDN2BAS with POAG suggests a role for TGFbeta signaling in glaucoma-related optic nerve disease. CDKN2BAS is an antisense RNA that regulates the expression of CDKN2B which is an inhibitor of the cell-cycle regulatory protein, CDK4.22 Decreased activity of CDK4 (due to increased CDKN2B caused by decreased expression of CDKN2BAS) promotes apoptosis. TGFbeta signaling also regulates CDKN2B23 suggesting that other proteins involved in the TGFbeta signaling pathway may regulate apoptosis and potentially influence optic nerve disease in glaucoma. Future work understanding the role of these pathways in optic nerve degeneration could reveal novel strategies for neuroprotection in glaucoma.

Most recently whole exome and whole genome sequencing technologies have successfully identified genes responsible for a variety of human ocular disorders.24-26 These powerful technologies will be another important tool facilitating future glaucoma gene discovery.

References

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  2. Ramdas WD, van Koolwijk LM, Ikram MK, Jansonius NM, de Jong PT, Bergen AA, Isaacs A, Amin N, Aulchenko YS, Wolfs RC, Hofman A, Rivadeneira F, Oostra BA, Uitterlinden AG, Hysi P, Hammond CJ, Lemij HG, Vingerling JR, Klaver CC, van Duijn CM. A genome-wide association study of optic disc parameters. PLoS Genet 2010; 6: e1000978.
  3. Macgregor S, Hewitt AW, Hysi PG, Ruddle JB, Medland SE, Henders AK, Gordon SD, Andrew T, McEvoy B, Sanfilippo PG, Carbonaro F, Tah V, Li YJ, Bennett SL, Craig JE, Montgomery GW, Tran-Viet KN, Brown NL, Spector TD, Martin NG, Young TL, Hammond CJ, Mackey DA. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 2010; 19: 2716-2724.
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  11. Fan BJ, Pasquale LR, Rhee D, Li T, Haines JL, Wiggs JL. LOXL1 promoter haplotypes are associated with exfoliation syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci 2011; 52: 2372-2378.
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