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Editors Selection IGR 13-2

Genetics: 11 new Copy Number Variations in POAG

Comment by Louis Pasquale on:

47974 Copy number variations and primary open-angle glaucoma, Davis LK; Meyer KJ; Schindler EI et al., Investigative ophthalmology & visual science, 2011; 52: 7122-7133

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Copy number variations (CNVs) represent structural changes in the genome where there are large deletions or insertions that can span many genes. CNVs are not uncommon and are thought to contribute to normal phenotypic variation. More importantly, they can contribute to human disease, particularly when they produce gene dose imbalances that upset normal homeostatic mechanisms. Davis et al. (1751) interrogated the human genome in 400 primary open-angle glaucoma (POAG) cases and 500 controls. They found 11 new CNVs that were only present in the POAG patients. The most common CNV was found in five cases. Some of these variants occurred in genomic regions where prior Mendelian approaches suggested that causative genetic variants for POAG existed.

In any gene association study phenotypic description of participants is of paramount importance. The authors' POAG definition seems reasonable but they neglect to indicate whether cases did not demonstrate features of secondary open-angle glaucoma. Furthermore, a majority of controls have age-related macular degeneration (AMD). While both AMD and POAG are age-related diseases, they probably do not share many other pathogenic features.

Detecting CNV is complicated but the authors do an excellent job in their search for these variants. They performed high throughput genotyping and then applied three different software packages to detect CNVs. The CNVs of interest were validated with follow-up PCR and genomic hybridization technology.

The study of copy number variants will complement the search for single nucleotide polymorphisms associated with POAG

It should be emphasized that the CNVs for POAG found in this study are rare and will not likely be the basis for a glaucoma genetic screening test. Also the arguments provided that any one of them are functional in POAG are somewhat speculative, but intriguing. Certainly the study of CNVs will complement the search for single nucleotide polymorphisms associated with POAG, as we continue to define the genetic architecture for POAG.

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