Common variants in CDKN2B-AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese

Abstract

Background: To date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated.

Methods and principal findings: We examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8 × 10(-10)). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)--POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)--and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients.

Conclusions and significance: In this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma.

Figure 1. Study design.

(A) We first performed the “Present GWAS” for POAG and identified the 9p21.3 locus. This result was confirmed by the combined analysis with the “Previous GWAS”. (B) We then subdivided the POAG subjects into two subtypes, POAG/HPG and POAG/NPG, and each group was analyzed by combining the two data sets in order to investigate the differences of statistical significance in the 9p21.3 locus.

Figure 2. Association results of the Present GWAS.

(A) The SNPs with a strong association appeared to exist in a cluster on chromosome 9 (red arrow). (B) The five significant SNPs that passed the Bonferroni correction threshold (horizontal dotted line) were identified in CDKN2B-AS1 on the 9p21 locus. SNP positions followed the NCBI Build 36 coordinates. The genetic recombination rates (cM/Mb) estimated by HapMap Project in Release 22 are indicated by the thin blue line.

Figure 3. Combined analysis of the Present and Previous GWAS data in 9p21.3 locus.

Three graphs representing the results of the association studies for POAG (A), HPG (B), and NPG (C) are shown in order from upper to lower, respectively. The results derived from the Present GWAS alone or the two combined GWAS data sets are indicated by the purple or green line graph plots, respectively. The lowest plot (D) shows an LD plot in the same region. All of the Present and Previous GWAS subject data was applied to draw the LD plot by Haploview v4.2. The color indicating pairwise r ² and LD block were lined by using the confidence interval (95%) of pairwise D′. Vertical dashed redline indicates the same region between the upper graphs and LD Block 1 and 2 at the lowest.