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

Yukihiro Shiga, Masato Akiyama, Koji M. Nishiguchi, Kota Sato, Nobuhiro Shimozawa, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Taiki Yamaji, Motoki Iwasaki, Shoichiro Tsugane, Isao Oze, Haruo Mikami, Mariko Naito, Kenji Wakai, Munemitsu Yoshikawa, Masahiro Miyake, Kenji Yamashiro, Japan Glaucoma Society Omics Group (JSG-OG)Kenji Kashiwagi, Takeshi Iwata, Fumihiko Mabuchi, Mitsuko Takamoto, Mineo Ozaki, Kazuhide Kawase, Makoto Aihara, Makoto Araie, Tetsuya Yamamoto, Yoshiaki Kiuchi, Makoto Nakamura, Yasuhiro Ikeda, Koh-Hei Sonoda, Tatsuro Ishibashi, Koji Nitta, Aiko Iwase, Shiroaki Shirato, Yoshitaka Oka, Mamoru Satoh, M Sasaki, Nobuo Fuse, Yoichi Suzuki, Ching-Yu Cheng, Chiea Chuen Khor, Mani Baskaran, Shamira Perera, Tin Aung, Eranga Vithana, Jessica N. Cooke Bailey, Jae H. Kang, Louis R. Pasquale, Jonathan L. Haines, NEIGHBORHOOD Consortium, Janey L. Wiggs, Kathryn P. Burdon, Puya Gharahkhani, Alex W. Hewitt, David A. Mackey, Stuart Macgregor, Jamie E. Craig, R. Rand Allingham, Micheal Hauser, Adeyinka Ashaye, Donald L. Budenz, Stephan Akafo, Susan E.I. Williams, Yoichiro Kamatani, Toru Nakazawa, Michiaki Kubo

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated 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.

Original languageEnglish
Pages (from-to)1486-1496
Number of pages11
JournalHuman Molecular Genetics
Volume27
Issue number8
DOIs
Publication statusPublished - 15 Apr 2018

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