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Cristina Venturini, Pirro Hysi, Abhishek Nag, Ekaterina Yonova, Jie Jin Wang, Tien Wong, Paul Healey, Paul Mitchell, Christopher Hammond, Ananth Viswanathan; Genetic factors and pathways affecting retinal nerve fiber layer thickness. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4500. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The Retinal nerve fiber layer (RNFL) thickness is used in the diagnosis of glaucoma and the assessment of progression or stability. Despite the known high heritability of RNFL thickness, the genes affecting this trait have not been extensively investigated. The aim of this study was to investigate genetic factors and pathways underlying RNFL thickness.
We carried out a genome wide association study (GWAS) on a panel of 2,617,903 SNPs imputed on the bases of the 1000 Genome for 964 individuals over the age of 49 years from the Blue Mountain Eye Study with quantitative measurements for RNFL thickness for the right eye. The regression analysis was corrected for age and sex. We also performed enrichment analysis with DAVID bioinformatics resources to extract putative biological mechanisms associated with the genes of interest.
No genome-wide significant results were obtained after multiple testing corrections. However, there are some strongly suggestive association signals. The first one is at rs1154119 on SLC25A21 on chromosome 14 (beta=0.04, p-value=2.41x10-7). This gene is part of the solute carrier family 25 and it is involved in transporting C5-C7 oxodicarboxylates across the inner membranes of mitochondria. Another suggestive association signal was found at rs2493383 (beta=0.01, p-value=1.67x10-6), which lies on SNX6 (chromosome 14). This gene is involved in several stages of intracellular trafficking and it promotes lysosomal degradation of Cdkn1B. Enrichment analysis shows an involvement of neuronal activity. The most significant pathway was axon guidance (p-value=0.003).
This study identified new suggestive association signals on chromosome 14 (SLC25A21 and SNX6) for retinal nerve fiber layer thickness. SNX6 promotes lysosomal degradation of Cdkn1B. This gene belongs to the same gene family of Cdkn2B which was previously associated with glaucoma and glaucoma endophenotypes such as vertical cup/disc ratio. Enrichment analysis appears to confirm the role of the genetic signals identified in this study in the determination of ganglion cell layer morphology and hence RNFL thickness.
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