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Editors Selection IGR 23-3

Genetics: Genomewide association studies in NTG

Comment by Janey Wiggs on:

26502 Genome-wide association study of normal tension glaucoma: Common variants in SRBD1 and ELOVL5 contribute to disease susceptibility, Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma Society; Meguro A; Inoko H et al., Ophthalmology, 2010; 117: 1331-1338

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Normal-tension glaucoma (NTG) is genetically complex, and it is likely that multiple genes and/or environmental factors can contribute to this condition. Genome-wide association studies (GWAS) have proved to be a successful approach for gene identification for common complex disorders. The study by Marita et al. (1245), reports the results of a GWAS using 305 normal-tension glaucoma patients and 355 unaffected gender-matched controls with the same age range as cases and from the same geographic region of Japan. Cases were more myopic (-4.03 ± 3.01 D) than controls (-3.00 D orless), however, a statistical comparison was not provided. 500,568 SNPs (single-nucleotide polymorphisms) distributed throughout the genome were analyzed for association with NTG. One SNP, rs321387 located in intron 17 of the SRBD1 (S1 RNA binding domain 1) gene met the bonferroni-corrected genome-wide criteria for statistical significance of 1x10^-7 with a p-value of 2.5x10^-9 (OR 2.8(1.96-3.99). The next best SNP (rs75860) located in the 5' UTR of the ELOVL5 (elongation of very long chain fatty acids) gene did not reach genome significance at a p-value of 4.1x10^-6 (1.69(1.36-2.11). Replication in a second case/control sample was not done. The SRBD1 gene product is known to facilitate splicing but does not have a clear role in retinal ganglion cell biology. The contribution of the gene product to NTG is also confused by the observation that the at-risk genotype of the significant SNP is associated with an increase in gene expression, while the protective genotype is associated with decreased expression. The mouse SRBD1 (Srba1) transcript is expressed in retinal ganglion cells.

In summary, a GWAS using a relatively small Japanese NTG case/control sample identified a single SNP (rs321387) in an intron of the SRBD1 gene that is statistically associated with the condition. Limitations of this study include the relatively small sample size, myopia as a potential confounder, and the lack of a replication study. Additional studies using a larger case/control sample and replication in other populations are necessary before the SRBD1 gene can beconfirmed as a NTG susceptibility gene.

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