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. 2018 Apr 15;27(8):1486-1496.
doi: 10.1093/hmg/ddy053.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma

Yukihiro Shiga  1   2 , Masato Akiyama  1 , Koji M Nishiguchi  2   3 , Kota Sato  2   4 , Nobuhiro Shimozawa  5 , Atsushi Takahashi  1   6 , Yukihide Momozawa  7 , Makoto Hirata  8 , Koichi Matsuda  9 , Taiki Yamaji  10 , Motoki Iwasaki  10 , Shoichiro Tsugane  11 , Isao Oze  12 , Haruo Mikami  13 , Mariko Naito  14 , Kenji Wakai  14 , Munemitsu Yoshikawa  15 , Masahiro Miyake  15 , Kenji Yamashiro  15   16 ; Japan Glaucoma Society Omics Group (JGS-OG); Kenji Kashiwagi  17 , Takeshi Iwata  18 , Fumihiko Mabuchi  17 , Mitsuko Takamoto  19 , Mineo Ozaki  20   21 , Kazuhide Kawase  22 , Makoto Aihara  19 , Makoto Araie  23 , Tetsuya Yamamoto  22 , Yoshiaki Kiuchi  24 , Makoto Nakamura  25 , Yasuhiro Ikeda  26 , Koh-Hei Sonoda  26 , Tatsuro Ishibashi  26 , Koji Nitta  27 , Aiko Iwase  28 , Shiroaki Shirato  29 , Yoshitaka Oka  30 , Mamoru Satoh  31 , Makoto Sasaki  31 , Nobuo Fuse  32 , Yoichi Suzuki  33 , Ching-Yu Cheng  34   35   36 , Chiea Chuen Khor  37 , Mani Baskaran  34   35 , Shamira Perera  34 , Tin Aung  34   35   36 , Eranga N Vithana  34 , Jessica N Cooke Bailey  38 , Jae H Kang  39 , Louis R Pasquale  40 , Jonathan L Haines  38 ; NEIGHBORHOOD Consortium; Janey L Wiggs  40 , Kathryn P Burdon  41   42 , Puya Gharahkhani  43 , Alex W Hewitt  44   45 , David A Mackey  41   46 , Stuart MacGregor  43 , Jamie E Craig  42 , R Rand Allingham  47 , Micheal Hauser  48 , Adeyinka Ashaye  49 , Donald L Budenz  50 , Stephan Akafo  51 , Susan E I Williams  52 , Yoichiro Kamatani  1   53 , Toru Nakazawa  2   3   4 , Michiaki Kubo  7
Affiliations

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma

Yukihiro Shiga et al. Hum Mol Genet. .

Abstract

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

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Figures

Figure 1.
Figure 1.
 Manhattan plot depicting the results of the genome-wide association study (GWAS) and replication studies in the Japanese population. The x-axis shows the chromosomes and their positions. The y-axis shows −log10 P-values of single nucleotide polymorphisms (SNPs). The orange horizontal line is the genome-wide significance level (P=5.0 × 10−8). Plots of the seven novel associated loci discovered by the Japanese GWAS are highlighted in red. Combined-analyses of the GWAS and Japanese replication sets are shown as diamonds for the loci which have not been reported in East Asians. Previously identified loci that showed a significant genome-wide significant association in the Japanese GWAS are highlighted in blue.
Figure 2.
Figure 2.
 Expression of positional candidate genes at novel primary open-angle glaucoma (POAG)-associated loci in ocular tissues. Expression of the positional candidate genes (ANKRD55, MAP3K1, LMX1B, LHPP, HMGA2, MEIS2) at five novel POAG-associated loci in different parts of the monkey eye. Two loci (FNDC3B, LOXL1) were used as positive controls because the expression of these genes was confirmed in the retina and the trabecular meshwork. Lysates from the COS-7 cell line were used as controls. The internal control gene was GAPDH.
See this image and copyright information in PMC

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