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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 34

Record: found
Abstract: found
Article: not found

Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

Gudmar Thorleifsson, Kristinn Magnusson, Patrick Sulem … (2007)

Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes. The population-attributable risk is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG.

0 comments Cited 202 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: found

Is Open Access

The Tohoku Medical Megabank Project: Design and Mission

(2016)

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

0 comments Cited 172 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Elastic fiber homeostasis requires lysyl oxidase-like 1 protein.

Hiromi Yanagisawa, Yun Zhao, Xiaoqing Liu … (2004)

Elastic fibers are components of the extracellular matrix and confer resilience. Once laid down, they are thought to remain stable, except in the uterine tract where cycles of active remodeling occur. Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema. Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance, but little is known about the role of renewal. Here we show that mice lacking the protein lysyl oxidase-like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. Thus elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a cross-linking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin.

0 comments Cited 157 times – based on 0 reviews      Review now

All references

Author and article information

Journal

Title: Human Molecular Genetics

Publisher: Oxford University Press (OUP)

ISSN (Print): 0964-6906

ISSN (Electronic): 1460-2083

Publication date Created: April 15 2018

Publication date Created: February 14 2018

Publication date Other: April 15 2018

Publication date (Print): April 15 2018

Publication date (Electronic): February 14 2018

Volume: 27

Issue: 8

Pages: 1486-1496

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

Article

DOI: 10.1093/hmg/ddy053

PMC ID: 6251544

PubMed ID: 29452408

SO-VID: 64547734-f366-49db-abc9-db0f67681a5c

License:

https://academic.oup.com/journals/pages/about_us/legal/notices

History

Data availability:

Comments

Comment on this article

Cited by 53

See all cited by

Most referenced authors 2,009

See all reference authors

- Version 1