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 (JGS-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; Makoto Sasaki; Nobuo Fuse; Yoichi Suzuki; Ching-Yu Cheng; Chiea Chuen Khor; Mani Baskaran; Shamira Perera; Tin Aung; Eranga N 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

doi:10.1093/hmg/ddy053

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

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

Authors

Yukihiro Shiga^{1

2}, Masato Akiyama¹, Koji M Nishiguchi^{2

3}, Kota Sato^{2

4}, Nobuhiro Shimozawa⁵, Atsushi Takahashi^{1

6}, Yukihide Momozawa⁷, Makoto Hirata⁸, Koichi Matsuda⁹, Taiki Yamaji¹⁰, Motoki Iwasaki¹⁰, Shoichiro Tsugane¹¹, Isao Oze¹², Haruo Mikami¹³, Mariko Naito¹⁴, Kenji Wakai¹⁴, Munemitsu Yoshikawa¹⁵, Masahiro Miyake¹⁵, Kenji Yamashiro^{15

16}; Japan Glaucoma Society Omics Group (JGS-OG); Kenji Kashiwagi¹⁷, Takeshi Iwata¹⁸, Fumihiko Mabuchi¹⁷, Mitsuko Takamoto¹⁹, Mineo Ozaki^{20

21}, Kazuhide Kawase²², Makoto Aihara¹⁹, Makoto Araie²³, Tetsuya Yamamoto²², Yoshiaki Kiuchi²⁴, Makoto Nakamura²⁵, Yasuhiro Ikeda²⁶, Koh-Hei Sonoda²⁶, Tatsuro Ishibashi²⁶, Koji Nitta²⁷, Aiko Iwase²⁸, Shiroaki Shirato²⁹, Yoshitaka Oka³⁰, Mamoru Satoh³¹, Makoto Sasaki³¹, Nobuo Fuse³², Yoichi Suzuki³³, Ching-Yu Cheng^{34

35

36}, Chiea Chuen Khor³⁷, Mani Baskaran^{34

35}, Shamira Perera³⁴, Tin Aung^{34

35

36}, Eranga N Vithana³⁴, Jessica N Cooke Bailey³⁸, Jae H Kang³⁹, Louis R Pasquale⁴⁰, Jonathan L Haines³⁸; NEIGHBORHOOD Consortium; Janey L Wiggs⁴⁰, Kathryn P Burdon^{41

42}, Puya Gharahkhani⁴³, Alex W Hewitt^{44

45}, David A Mackey^{41

46}, Stuart MacGregor⁴³, Jamie E Craig⁴², R Rand Allingham⁴⁷, Micheal Hauser⁴⁸, Adeyinka Ashaye⁴⁹, Donald L Budenz⁵⁰, Stephan Akafo⁵¹, Susan E I Williams⁵², Yoichiro Kamatani^{1

53}, Toru Nakazawa^{2

3

4}, Michiaki Kubo⁷

Affiliations

¹ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
² Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
³ Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
⁴ Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
⁵ Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
⁶ Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁷ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸ Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁹ Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁰ Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
¹¹ Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
¹² Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
¹³ Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan.
¹⁴ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹⁵ Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
¹⁶ Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan.
¹⁷ Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
¹⁸ Division of Molecular and Cellular Biology, National Institute of Sensory Organs, Tokyo Medical Center, National Hospital Organization, Tokyo, Japan.
¹⁹ Department of Ophthalmology, University of Tokyo, Tokyo, Japan.
²⁰ Ozaki Eye Hospital, Hyuga, Miyazaki, Japan.
²¹ Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
²² Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan.
²³ Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan.
²⁴ Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan.
²⁵ Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
²⁶ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²⁷ Fukuiken Saiseikai Hospital, Fukui, Japan.
²⁸ Tajimi Iwase Eye Clinic, Tajimi, Japan.
²⁹ Yotsuya Shirato Eye Clinic, Tokyo, Japan.
³⁰ Oka Eye Clinic, Fukuoka, Japan.
³¹ Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
³² Department of Integrative Genomics, Tohoku Medical Megabank Organization, Miyagi, Japan.
³³ Department of Education and Training, Tohoku Medical Megabank Organization, Miyagi, Japan.
³⁴ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
³⁵ Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore.
³⁶ Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁷ Genome Institute of Singapore, Singapore.
³⁸ Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
³⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
⁴¹ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
⁴² Department of Ophthalmology, Flinders University, Adelaide, SA, Australia.
⁴³ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁴⁴ Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia.
⁴⁵ Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia.
⁴⁶ Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, WA, Australia.
⁴⁷ Department of Ophthalmology, Duke University, Durham, NC, USA.
⁴⁸ Duke University Medical Center, Durham, NC, USA.
⁴⁹ Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
⁵⁰ Department of Ophthalmology, University of North Carolina at Chapel Hill, USA.
⁵¹ University of Ghana School of Medicine and Dentistry, Ghana.
⁵² Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, South Africa.
⁵³ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asian People
Black People
Cardiovascular Diseases / complications
Cardiovascular Diseases / ethnology
Cardiovascular Diseases / genetics*
Cardiovascular Diseases / pathology
Case-Control Studies
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / ethnology
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / pathology
ErbB Receptors / genetics
ErbB Receptors / metabolism
Eye Proteins / genetics*
Eye Proteins / metabolism
Female
Gene Expression
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Glaucoma, Open-Angle / complications
Glaucoma, Open-Angle / ethnology
Glaucoma, Open-Angle / genetics*
Glaucoma, Open-Angle / pathology
Humans
Male
Mutation
Polymorphism, Single Nucleotide
Signal Transduction
White People

Substances

Eye Proteins
EGFR protein, human
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding