Glaucoma Opinion IGR 10-2

Glaucoma Genetics: Where are we?

Subhabrata Chakrabarti, Hyderabad, India

Preamble: The glaucoma’s comprise a chronic and progressive group of hete-rogeneous optic neuropathies along with visual field defects.1 Raised intraocular pressure (IOP) may confer a significant risk to glaucoma.2 The underlying eti-ology is complex in nature and the molecular mechanisms are still unclear.3 Several risk factors such as age, gender, family history of the disease, systemic conditions and ethnicity have been sug-gested that enhances the susceptibility to glaucoma in varying degrees across populations.4-6 The mode of inheritance in adult-onset primary open angle (POAG) and primary angle-closure glaucoma’s (PACG) are complex in nature. This has been a major impediment in identifying large affected families for gene mapping by conventional linkage analysis.7 However, the hereditary component in juvenile-onset POAG facilitated the mapping of some candidate loci.8

Congenital and developmental glaucomas largely follow a Mendelian pattern with autosomal dominant and autosomal recessive modes of inheritance. Thus, co-segregation of candidate gene mutations among the affected subjects in such families could be thoroughly deciphered.9-11

The lack of identification of all the genes involved at various stages of glaucoma pathophysiology has restricted the understanding of gene-gene interactions as well as genotype-phenotype correlation in glaucoma
The adult-onset primary glaucoma’s constitute a major proportion of all glaucoma’s and are attributed to multiple genes with varying magnitudes of effect.3,6 Gene mapping in these disorders is a ma-jor challenge in modern biology. The successes of new-generation technologies and microarray-based high-throughput screening plat-forms have generated tremendous hope towards understanding the molecular genetic mechanisms in these disorders. Current status: Molecular genetic studies in POAG led to the identification of more than 15 chromosomal loci by linkage.12 But only three genes, namely MYOC,13 optineurin (OPTN)14 and WDR36,15 have been characterized, that harbor disease-associated mutations with high degrees of allelic heterogeneity in different populations. The mutation spectrum in these genes does not explain the overall genetic contribution in glaucoma pathogenesis. Variable penetrence and expressivity of the gene mutation further compounds the problem of understanding the underlying molecular mechanism. Genes involved in congenital and developmental glaucomas, such as CYP1B1, have also exhibited some degrees of involvement in adult-onset primary glaucoma’s.16 While this could be attributed to certain similarities in the phenotypic manifestations (such as raised IOP) or in the biochemical pathway, their functions remain to be elucidated. Further analysis has revealed that mutations in CYP1B1 across multiple glaucoma phenotypes are strongly structured by their genetic signatures or haplotypes irrespective of geographical locations, which may have implications in devising molecular diagnostics.11,16

Only three genes, namely MYOC, optineurin (OPTN) and WDR36, have been characterized, that harbor disease-associated mutations with high degrees of allelic heterogeneity in different populations
Other than genes harboring the glaucoma-linked loci, variants in more than twenty candidate genes involved in certain physiological mechanisms have been associated with POAG.12 These comprise genes involved in oxidative stress, aqueous humor outflow pathway, extra cellular matrix protein remodeling and in retinal ganglion cell death.3 But these studies could hardly be replicated across different populations. Non-association of gene variant(s) could be attributed to multiple issues pertaining to the study power, sample size, effect size of the variant and more importantly the phenotype of the cases and the matching of controls to avoid population sub-structuring. Some recent studies have used quantitative traits such as IOP to map genes. These approaches have efficiently demonstrated a better means of identifying the candidate loci, but the corresponding genes are yet to be identified.17,18
A major impediment in understanding the genetics of glaucoma has been the lack of identification of all the genes involved at various stages of glaucoma pathophysiology. This has restricted the under-standing of gene-gene interactions as well as genotype-phenotype correlation in glaucomatous conditions.

In the near future, WGA in primary glaucoma’s with densely linked SNPs covering the entire genome on high throughput micro array platforms would be the method of choice
Future prospects: Recently, a whole genome association (WGA) in an endogamous population isolate (Icelandic population) led to the identification of the lysyl oxidase gene (LOXL1) in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG).19 These findings were also replicated across multiple populations worldwide.20 Although the XFS-associated single nucleotide polymorphisms (SNPs) exhibited a high population attributable risk, they were also observed in relatively higher frequency in the general population. While that may restrict its potential use as marker for predictive testing, this was a major breakthrough in identifying a gene in a glaucomatous condition.

In the near future, WGA in primary glaucomas with densely linked SNPs covering the entire genome on high throughput micro array platforms would be the method of choice.21 Additionally, finding structural variations within the genome would help in the identification of specific mutations leading to these conditions. These analyses provide a better and faster means of mapping genes when performed in isolated and inbred populations that are restricted to admixture and gene flow from other populations. Moreover, the haplotypes in these populations are conserved and rarely differentiated by genetic recombinations. WGA facilitates a huge generation of genomic data that would lead to understanding their associations with specific phenotypic conditions, which may be potential risk factors for glaucoma susceptibility. Understanding the interaction of these variants in combination would provide further insight into glaucoma pathogenesis that would have implications for predictive testing in populations.


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