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Editors Selection IGR 12-4

Genetics: Genetic underpinnings of OD morphology

Comment by Rand Allingham on:

27580 A genome-wide association study of optic disc parameters, Ramdas WD; van Koolwijk LM; Ikram MK et al., PLoS Genetics, 2010; 6: e1000978

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In this important paper Ramdas et al. (1579) examine the genetic underpinnings optic disc morphology. The datasets utilized to perform gene discovery and replication included 7360 and 4455 participants, respectively. Of note, extremely robust associations were noted between the genomic regions containing CDC7/TGFBR3, ATOH7, and SALL1 and optic disc area. Seven genomic loci, including CDKN2B, SIX1, SCYL1, CHEK2, ATOH7, and DCLK1, demonstrated association with vertical cup- disc ratio (VCDR). Only one genetic locus, ATOH7, was associated with both optic disc area and VCDR. The result would seemingly support the concept that the genetic architecture that sub serves the development and maturation of these optic disc parameters only partially overlap. Whereas ATOH7 is expressed in the retina, including photoreceptors and retinal ganglion cells, other associated genes or genes within the associated genomic region have a wide variety of known functions. These include regulation of cell division cycle, interaction with the TGF-β superfamily, and a host of other genes and gene pathways. This underscores the complexity of the optic disc phenotype and intimates the vast number of genes that interact to produce remarkably confined phenotypic traits.

Clearly of great interest is whether these genetic associations, based on quantitative traits found in a normal population, play a role in the pathogenesis of diseases such as glaucoma or other optic neuropathies. The investigators were unable to identify an association with optic nerve diseases in this dataset, likely due to insufficient power. However the role of these genes in glaucoma and other neuropathies will undoubtedly be examined by many researchers. It will be interesting to see whether genes primarily related to the development of the optic nerve head will play a role in diseases of later life. Perhaps on a more sobering note, it was found that the aggregate genetic association for the three major SNPs for optic disc area and the six loci for VCDR account for only 2.7% and 2.2% of the phenotypic variability of these traits. This leaves the vast majority of the genetic substructure for these traits unexplained. This demonstrates the need to construct larger clinical datasets containing phenotype data that is increasingly refined to power the investigations that lie ahead.

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