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Open-Angle Glaucoma: HELP
Articles by Alex W. Hewitt
Based on 44 articles published since 2010
(Why 44 articles?)
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Between 2010 and 2020, A. W. Hewitt wrote the following 44 articles about Glaucoma, Open-Angle.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Peeking into the molecular trove of discarded surgical specimens. 2016

Hewitt, Alex W / Cook, Anthony L / Pébay, Alice. ·Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, Australia. ·Clin Exp Ophthalmol · Pubmed #27870490.

ABSTRACT: -- No abstract --

2 Review Genome-wide association study success in ophthalmology. 2014

Mackey, David A / Hewitt, Alex W. ·aLions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia bCentre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria cSchool of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia. ·Curr Opin Ophthalmol · Pubmed #25014751.

ABSTRACT: PURPOSE OF REVIEW: Much progress in our understanding of the genetic profile of many ophthalmic diseases has been made over the last decade. Identification of novel gene associations allows insight into the mechanisms of disease and potentially enables the identification of individuals at increased risk, as well as facilitating the development of new treatments. We highlight key recent discoveries using the genome-wide association study design. RECENT FINDINGS: Over the last 2 years, we have seen major international collaborations successfully conduct genome-wide association study to identify genetic pathways associated with eye diseases, such as myopia, age-related macular degeneration and glaucoma. Similarly other studies have identified and confirmed genes associated with ocular biometry or disease-specific endophenotypes. SUMMARY: Our understanding of the genetic architecture of common eye diseases, such as myopia, age-related macular degeneration and glaucoma, is rapidly expanding. With reducing costs of next-generation sequencing, we expect a transition to large-scale interrogation at the whole exome and genome level, which will enable the identification of rare variants which confer a level of sensitivity and specificity to predict risk that will allow us to further understand, predict and intervene in genetic-based eye diseases.

3 Article Effect of phacoemulsification cataract surgery on intraocular pressure in early glaucoma: A prospective multi-site study. 2020

Qassim, Ayub / Walland, Mark J / Landers, John / Awadalla, Mona / Nguyen, Thi / Loh, Jason / Schulz, Angela M / Ridge, Bronwyn / Galanopoulos, Anna / Agar, Ashish / Hewitt, Alex W / Graham, Stuart L / Healey, Paul R / Casson, Robert J / Craig, Jamie E. ·Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia. · Glaucoma Investigation and Research Unit, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia. · South Australian Institute of Ophthalmology, Royal Adelaide Hospital, Adelaide, New South Wales, Australia. · Department of Ophthalmology, Prince of Wales Hospital, Sydney, New South Wales, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. · South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia. ·Clin Exp Ophthalmol · Pubmed #32031310.

ABSTRACT: IMPORTANCE: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG. BACKGROUND: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up. DESIGN: Prospective, multicentre, matched case-control Australian study. PARTICIPANTS: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes. METHODS: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data. MAIN OUTCOME MEASURES: Change in IOP. RESULTS: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P < .001) with 59 eyes (34%) achieving at least 3 mmHg reduction. Compared to matched controls, the mean reduction in IOP was 1.75 mmHg (95% confidence interval 1.15-2.33 mmHg; P < .001). Higher preoperative IOP and being on fewer topical glaucoma medications preoperatively were strongly predictive of a larger IOP reduction in a multivariable model. Anterior chamber depth was not associated with IOP reduction. Eyes with preoperative IOP ≥24 mmHg had a mean IOP reduction of 4.03 mmHg with 81% experiencing at least 3 mmHg reduction. Sub-analysis of medication naïve and pseudoexfoliation patients showed similar results. CONCLUSIONS AND RELEVANCE: Cataract surgery has a confirmed effect in reducing IOP in a "real world" setting of early glaucoma patients.

4 Article Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes. 2019

Laville, Vincent / Kang, Jae H / Cousins, Clara C / Iglesias, Adriana I / Nagy, Réka / Cooke Bailey, Jessica N / Igo, Robert P / Song, Yeunjoo E / Chasman, Daniel I / Christen, William G / Kraft, Peter / Rosner, Bernard A / Hu, Frank / Wilson, James F / Gharahkhani, Puya / Hewitt, Alex W / Mackey, David A / Hysi, Pirro G / Hammond, Christopher J / vanDuijn, Cornelia M / Haines, Jonathan L / Vitart, Veronique / Fingert, John H / Hauser, Michael A / Aschard, Hugues / Wiggs, Janey L / Khawaja, Anthony P / MacGregor, Stuart / Pasquale, Louis R / Anonymous1151190 / Anonymous1161190 / Anonymous1171190. ·Department of Computational Biology, Institut Pasteur, Paris, France. · Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. · Departments of Ophthalmology and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. · Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. · Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. · Division of Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA. · Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA. · Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA; Department of Nutrition, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom. · Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia. · Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom. · Departments of Ophthalmology and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa, USA. · Departments of Ophthalmology and Medicine, Duke University, Durham, North Carolina, USA. · Department of Computational Biology, Institut Pasteur, Paris, France; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, USA. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. · Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: Louis.Pasquale@mssm.edu. ·Am J Ophthalmol · Pubmed #31121135.

ABSTRACT: PURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (r RESULTS: Overall, there was little r CONCLUSION: These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.

5 Article Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies. 2019

Han, Xikun / Souzeau, Emmanuelle / Ong, Jue-Sheng / An, Jiyuan / Siggs, Owen M / Burdon, Kathryn P / Best, Stephen / Goldberg, Ivan / Healey, Paul R / Graham, Stuart L / Ruddle, Jonathan B / Mills, Richard A / Landers, John / Galanopoulos, Anna / White, Andrew J R / Casson, Robert / Mackey, David A / Hewitt, Alex W / Gharahkhani, Puya / Craig, Jamie E / MacGregor, Stuart. ·Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia. · School of Medicine, University of Queensland, St Lucia, Brisbane, Australia. · Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand. · Discipline of Ophthalmology, Sydney Eye Hospital, University of Sydney, Sydney, Australia. · Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. · Ophthalmology and Vision Science, Faculty of Medicine and Human Sciences, Macquarie University, Australia. · Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia. · Ophthalmology, University of Melbourne, Department of Surgery, Melbourne, Australia. · Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia. · South Australian Institute of Ophthalmology, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia. · Centre for Ophthalmology and Visual Sciences, Lions Eye Institute, University of Western Australia, Perth, Australia. ·JAMA Ophthalmol · Pubmed #30267046.

ABSTRACT: Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). Design, Setting, and Participants: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. Main Outcomes and Measures: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. Results: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. Conclusions and Relevance: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

6 Article Mitochondrial DNA Variation and Disease Susceptibility in Primary Open-Angle Glaucoma. 2018

Singh, Larry N / Crowston, Jonathan G / Lopez Sanchez, M Isabel G / Van Bergen, Nicole J / Kearns, Lisa S / Hewitt, Alex W / Yazar, Seyhan / Mackey, David A / Wallace, Douglas C / Trounce, Ian A. ·Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, University of Pennsylvania, Philadelphia, United States. · Center for Eye Research Australia, Ophthalmology, University of Melbourne Department of Surgery, Melbourne, Australia. · Menzies Research Institute Tasmania, School of Medicine, University of Tasmania, Hobart, Australia. · Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Australia. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States. ·Invest Ophthalmol Vis Sci · Pubmed #30242360.

ABSTRACT: Purpose: To determine whether mitochondrial DNA haplogroups or rare variants associate with primary open-angle glaucoma in subjects of European descent. Methods: A case-control comparison of age- and sex-matched cohorts of 90 primary open-angle glaucoma patients and 95 population controls. Full mitochondrial DNA sequences from peripheral blood were generated by next-generation sequencing and compared to the revised Cambridge Reference Sequence to define mitochondrial haplogroups and variants. Results: Most subjects were of the major European haplogroups H, J, K, U, and T. Logistic regression analysis showed haplogroup U to be significantly underrepresented in male primary open-angle glaucoma subjects (odds ratio 0.25; 95% confidence interval [CI] 0.09-0.67; P = 0.007; Bonferroni multiple testing P = 0.022). Variants in the mitochondrial DNA gene MT-ND2 were overrepresented in the control group (P = 0.005; Bonferroni multiple testing correction P = 0.015). Conclusions: Mitochondrial DNA ancestral lineages modulate the risk for primary open-angle glaucoma in populations of European descent. Haplogroup U and rare variants in the mitochondrial DNA-encoded MT-ND2 gene may be protective against primary open-angle glaucoma. Larger studies are warranted to explore haplogroup associations with disease risk in different ethnic groups and define biomarkers of primary open-angle glaucoma endophenotypes to target therapeutic strategies.

7 Article Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. 2018

Iglesias, Adriana I / Mishra, Aniket / Vitart, Veronique / Bykhovskaya, Yelena / Höhn, René / Springelkamp, Henriët / Cuellar-Partida, Gabriel / Gharahkhani, Puya / Bailey, Jessica N Cooke / Willoughby, Colin E / Li, Xiaohui / Yazar, Seyhan / Nag, Abhishek / Khawaja, Anthony P / Polašek, Ozren / Siscovick, David / Mitchell, Paul / Tham, Yih Chung / Haines, Jonathan L / Kearns, Lisa S / Hayward, Caroline / Shi, Yuan / van Leeuwen, Elisabeth M / Taylor, Kent D / Anonymous531121 / Bonnemaijer, Pieter / Rotter, Jerome I / Martin, Nicholas G / Zeller, Tanja / Mills, Richard A / Souzeau, Emmanuelle / Staffieri, Sandra E / Jonas, Jost B / Schmidtmann, Irene / Boutin, Thibaud / Kang, Jae H / Lucas, Sionne E M / Wong, Tien Yin / Beutel, Manfred E / Wilson, James F / Anonymous541121 / Anonymous551121 / Uitterlinden, André G / Vithana, Eranga N / Foster, Paul J / Hysi, Pirro G / Hewitt, Alex W / Khor, Chiea Chuen / Pasquale, Louis R / Montgomery, Grant W / Klaver, Caroline C W / Aung, Tin / Pfeiffer, Norbert / Mackey, David A / Hammond, Christopher J / Cheng, Ching-Yu / Craig, Jamie E / Rabinowitz, Yaron S / Wiggs, Janey L / Burdon, Kathryn P / van Duijn, Cornelia M / MacGregor, Stuart. ·Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands. · University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, F-33000, Bordeaux, France. · Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK. · Regenerative Medicine Institute and Department of Surgery, Cedars-Sinai Medical Center, CA 90048, Los Angeles, CA, USA. · Cornea Genetic Eye Institute, CA 90048, Los Angeles, CA, USA. · Department of Ophthalmology, University Medical Center Mainz, 55131, Mainz, Germany. · Department of Ophthalmology, Inselspital, University Hospital Bern, University of Bern, Bern, CH-3010, Switzerland. · Statistical Genetics, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia. · Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH 44106, Cleveland, OH, USA. · Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, 44106, USA. · Biomedical Sciences Research Institute, Ulster University, BT52 1SA, Belfast, Northern Ireland, UK. · Royal Victoria Hospital, Belfast Health and Social Care Trust, BT12 6BA, Belfast, Northern Ireland, UK. · Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90509, CA, USA. · Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, CA, USA. · Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, WA 6009, Perth, WA, Australia. · Department of Twin Research and Genetic Epidemiology, King's College London, WC2R 2LS, London, UK. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, CB2 0SR, Cambridge, UK. · NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, EC1V 9EL, London, UK. · Faculty of Medicine, University of Split, HR-21000, Split, Croatia. · Departments of Medicine and Epidemiology and Cardiovascular Health Research Unit, University of Washington, WA 98101, Washington, USA. · The New York Academy of Medicine, NY 10029, New York, NY, USA. · Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, NSW 2145, Sydney, NSW, Australia. · Singapore Eye Research Institute, Singapore National Eye Centre, 168751, Singapore, Singapore. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, VIC 3002, East Melbourne, Australia. · Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia. · Department of General and Interventional Cardiology, University Heart Center Hamburg, 20251, Hamburg, Germany. · German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246, Hamburg, Germany. · Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia. · Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, 68167, Mannheim, Germany. · Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, 55131, Mainz, Germany. · Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, MA, USA. · Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, TAS, Australia. · Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, 169857, Singapore, Singapore. · Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117549, Singapore. · Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Mainz, Mainz, 55131, Germany. · Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, EH16 4UX, Edinburgh, UK. · Department of Internal Medicine, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands. · Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, 2593 HW, The Hague, The Netherlands. · School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, TAS, Australia. · Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672, Singapore. · Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, MA, USA. · Institute for Molecular Bioscience, University of Queensland, QLD 4067, Brisbane, Australia. · Department of Ophthalmology, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands. · Statistical Genetics, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia. Stuart.MacGregor@qimrberghofer.edu.au. ·Nat Commun · Pubmed #29760442.

ABSTRACT: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10

8 Article Uteroglobin and FLRG concentrations in aqueous humor are associated with age in primary open angle glaucoma patients. 2018

Ashworth Briggs, Esther L / Toh, Tze'Yo / Eri, Rajaraman / Hewitt, Alex W / Cook, Anthony L. ·School of Health Sciences, University of Tasmania, Launceston, Australia. · Launceston Eye Institute and Launceston Eye Doctors, Launceston, Australia. · Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia. · School of Health Sciences, University of Tasmania, Launceston, Australia. anthony.cook@utas.edu.au. · Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, 7001, Australia. anthony.cook@utas.edu.au. ·BMC Ophthalmol · Pubmed #29482497.

ABSTRACT: BACKGROUND: The pathophysiological changes occurring in the trabecular meshwork in primary open angle glaucoma are poorly understood, but are thought to include increased extracellular matrix deposition, trabecular meshwork cell apoptosis, inflammation, trabecular meshwork calcification and altered protein composition of the aqueous humor. Although many proteins are present in aqueous humor, relatively few have been studied extensively, and their potential roles in primary open angle glaucoma are unknown. METHODS: Analyte concentrations in aqueous humor from 19 primary open angle glaucoma and 18 cataract patients were measured using a multiplex immunoassay. Fisher's exact test was used to assess statistical significance between groups, and correlations of analyte concentrations with age, intraocular pressure, pattern standard deviation, mean deviation, cup-to-disc ratio and disease duration since commencing treatment were tested by Spearman's method. RESULTS: CHI3L1, FLRG, HGF, MIF, P-selectin and Uteroglobin were detected in more than 50% of samples of one or both patient groups, some of which have not previously been quantified in aqueous humor. In the glaucoma but not the cataract group, significant correlations were determined with age for Uteroglobin/SCGB1A1 (r CONCLUSIONS: The correlations of uteroglobin and FLRG with age in primary open angle glaucoma but not cataract may suggest a heightened requirement for anti-inflammatory (uteroglobin) or anti-calcification (FLRG) activity in the ageing glaucomatous trabecular meshwork.

9 Article Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. 2018

Shiga, Yukihiro / Akiyama, Masato / Nishiguchi, Koji M / Sato, Kota / Shimozawa, Nobuhiro / Takahashi, Atsushi / Momozawa, Yukihide / Hirata, Makoto / Matsuda, Koichi / Yamaji, Taiki / Iwasaki, Motoki / Tsugane, Shoichiro / Oze, Isao / Mikami, Haruo / Naito, Mariko / Wakai, Kenji / Yoshikawa, Munemitsu / Miyake, Masahiro / Yamashiro, Kenji / Anonymous1110937 / Kashiwagi, Kenji / Iwata, Takeshi / Mabuchi, Fumihiko / Takamoto, Mitsuko / Ozaki, Mineo / Kawase, Kazuhide / Aihara, Makoto / Araie, Makoto / Yamamoto, Tetsuya / Kiuchi, Yoshiaki / Nakamura, Makoto / Ikeda, Yasuhiro / Sonoda, Koh-Hei / Ishibashi, Tatsuro / Nitta, Koji / Iwase, Aiko / Shirato, Shiroaki / Oka, Yoshitaka / Satoh, Mamoru / Sasaki, Makoto / Fuse, Nobuo / Suzuki, Yoichi / Cheng, Ching-Yu / Khor, Chiea Chuen / Baskaran, Mani / Perera, Shamira / Aung, Tin / Vithana, Eranga N / Cooke Bailey, Jessica N / Kang, Jae H / Pasquale, Louis R / Haines, Jonathan L / Anonymous1120937 / Wiggs, Janey L / Burdon, Kathryn P / Gharahkhani, Puya / Hewitt, Alex W / Mackey, David A / MacGregor, Stuart / Craig, Jamie E / Allingham, R Rand / Hauser, Micheal / Ashaye, Adeyinka / Budenz, Donald L / Akafo, Stephan / Williams, Susan E I / Kamatani, Yoichiro / Nakazawa, Toru / Kubo, Michiaki. ·Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. · Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan. · Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan. · Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan. · Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan. · Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan. · Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. · Institute of Medical Science, The University of Tokyo, Tokyo, Japan. · Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. · Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan. · Center for Public Health Sciences, National Cancer Center, Tokyo, Japan. · Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. · Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan. · Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan. · Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. · Division of Molecular and Cellular Biology, National Institute of Sensory Organs, Tokyo Medical Center, National Hospital Organization, Tokyo, Japan. · Department of Ophthalmology, University of Tokyo, Tokyo, Japan. · Ozaki Eye Hospital, Hyuga, Miyazaki, Japan. · Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. · Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan. · Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan. · Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan. · Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. · Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Fukuiken Saiseikai Hospital, Fukui, Japan. · Tajimi Iwase Eye Clinic, Tajimi, Japan. · Yotsuya Shirato Eye Clinic, Tokyo, Japan. · Oka Eye Clinic, Fukuoka, Japan. · Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan. · Department of Integrative Genomics, Tohoku Medical Megabank Organization, Miyagi, Japan. · Department of Education and Training, Tohoku Medical Megabank Organization, Miyagi, Japan. · Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. · Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore. · Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · Genome Institute of Singapore, Singapore. · Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. · Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. · Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia. · Department of Ophthalmology, Flinders University, Adelaide, SA, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. · Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia. · Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, WA, Australia. · Department of Ophthalmology, Duke University, Durham, NC, USA. · Duke University Medical Center, Durham, NC, USA. · Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria. · Department of Ophthalmology, University of North Carolina at Chapel Hill, USA. · University of Ghana School of Medicine and Dentistry, Ghana. · Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, South Africa. · Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. ·Hum Mol Genet · Pubmed #29452408.

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.

10 Article Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. 2018

Gharahkhani, Puya / Burdon, Kathryn P / Cooke Bailey, Jessica N / Hewitt, Alex W / Law, Matthew H / Pasquale, Louis R / Kang, Jae H / Haines, Jonathan L / Souzeau, Emmanuelle / Zhou, Tiger / Siggs, Owen M / Landers, John / Awadalla, Mona / Sharma, Shiwani / Mills, Richard A / Ridge, Bronwyn / Lynn, David / Casson, Robert / Graham, Stuart L / Goldberg, Ivan / White, Andrew / Healey, Paul R / Grigg, John / Lawlor, Mitchell / Mitchell, Paul / Ruddle, Jonathan / Coote, Michael / Walland, Mark / Best, Stephen / Vincent, Andrea / Gale, Jesse / RadfordSmith, Graham / Whiteman, David C / Montgomery, Grant W / Martin, Nicholas G / Mackey, David A / Wiggs, Janey L / MacGregor, Stuart / Craig, Jamie E / Anonymous320937. ·QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Puya.Gharahkhani@qimrberghofer.edu.au. · University of Tasmania, Hobart, Tasmania, Australia. · Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. · South Australian Health & Medical Research Institute, School of Medicine, Flinders University, Adelaide, South Australia, Australia. · South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia. · Ophthalmology and Vision Science, Macquarie University, Sydney, New South Wales, Australia. · Department of Ophthalmology, University of Sydney, Sydney, Australia. · Centre for Vision Research, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia. · Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Department of Ophthalmology, University of Auckland, Auckland, New Zealand. · Department of Ophthalmology, University of Otago, Dunedin, Otago, New Zealand. · School of Medicine, University of Queensland, Herston Campus, Brisbane, QLD, Australia. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. jamie.craig@flinders.edu.au. ·Sci Rep · Pubmed #29449654.

ABSTRACT: Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

11 Article Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. 2018

Bailey, Jessica N Cooke / Gharahkhani, Puya / Kang, Jae H / Butkiewicz, Mariusz / Sullivan, David A / Weinreb, Robert N / Aschard, Hugues / Allingham, R Rand / Ashley-Koch, Allison / Lee, Richard K / Moroi, Sayoko E / Brilliant, Murray H / Wollstein, Gadi / Schuman, Joel S / Fingert, John H / Budenz, Donald L / Realini, Tony / Gaasterland, Terry / Scott, William K / Singh, Kuldev / Sit, Arthur J / Igo, Robert P / Song, Yeunjoo E / Hark, Lisa / Ritch, Robert / Rhee, Douglas J / Vollrath, Douglas / Zack, Donald J / Medeiros, Felipe / Vajaranant, Thasarat S / Chasman, Daniel I / Christen, William G / Pericak-Vance, Margaret A / Liu, Yutao / Kraft, Peter / Richards, Julia E / Rosner, Bernard A / Hauser, Michael A / Craig, Jamie E / Burdon, Kathryn P / Hewitt, Alex W / Mackey, David A / Haines, Jonathan L / MacGregor, Stuart / Wiggs, Janey L / Pasquale, Louis R / Anonymous3121159. ·Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States. · Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States. · Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia. · Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States. · Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States. · Department of Ophthalmology, Hamilton Glaucoma Center and Shiley Eye Institute, University of California at San Diego, La Jolla, California, United States. · Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, United States. · Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States. · Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States. · Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States. · Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, Wisconsin, United States. · Department of Ophthalmology, NYU Langone Medical Center, NYU School of Medicine, New York, New York, United States. · Departments of Ophthalmology and Anatomy/Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, United States. · Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, United States. · Department of Ophthalmology, WVU Eye Institute, Morgantown, West Virginia, United States. · Scripps Genome Center, University of California at San Diego, San Diego, California, United States. · Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States. · Department of Ophthalmology, Stanford University, Palo Alto, California, United States. · Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States. · Wills Eye Hospital, Glaucoma Research Center, Philadelphia, Pennsylvania, United States. · Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, United States. · Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States. · Department of Genetics, Stanford University, Palo Alto, California, United States. · Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, United States. · Department of Ophthalmology, University of Illinois College of Medicine at Chicago, Chicago, Illinois, United States. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States. · Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States. · Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts, United States. · Department of Ophthalmology, Flinders University, Adelaide, SA, Australia. · School of Medicine, Menzies Research Institute of Tasmania, Hobart, Australia. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia. · Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States. ·Invest Ophthalmol Vis Sci · Pubmed #29392307.

ABSTRACT: Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

12 Article Expression QTL analysis of glaucoma endophenotypes in the Norfolk Island isolate provides evidence that immune-related genes are associated with optic disc size. 2018

Fang Kho, Pik / Lea, Rodney A / Benton, Miles C / Eccles, David / Haupt, Larisa M / Hewitt, Alex W / Sherwin, Justin C / Mackey, David A / Griffiths, Lyn R. ·Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. · Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, University of Melbourne, East Melbourne, VIC, Australia. · Institute for Medical Research, School of Medicine, Menzies University of Tasmania, Hobart, TAS, Australia. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA, Australia. · Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. lyn.griffiths@qut.edu.au. ·J Hum Genet · Pubmed #29215094.

ABSTRACT: Primary open-angle glaucoma (POAG) is influenced by both genetic and environmental factors. Despite significant progress in identifying genetic variants associated with POAG, there remains a substantial amount of unexplained heritability. Study design features that may enhance knowledge of the genetic architecture include focusing on multiple quantitative traits related to ocular disorders (i.e. endophenotypes), targeting genetic variants that directly influence gene expression (i.e. cis-eQTLs) and utilising genetically isolated populations to reduce genetic and environmental noise and thus enhance association signals. In this study we performed heritability and blood-based eQTL association analysis of five key POAG endophenotypes in 330 individuals from the Norfolk Island (NI) isolate. Results showed evidence of heritability for all five traits, with H

13 Article Genome-wide linkage and association analysis of primary open-angle glaucoma endophenotypes in the Norfolk Island isolate. 2017

Matovinovic, Elizabeth / Kho, Pik Fang / Lea, Rodney A / Benton, Miles C / Eccles, David A / Haupt, Larisa M / Hewitt, Alex W / Sherwin, Justin C / Mackey, David A / Griffiths, Lyn R. ·Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia. · Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, University of Melbourne, East Melbourne, Victoria, Australia. · Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia. ·Mol Vis · Pubmed #28966548.

ABSTRACT: PURPOSE: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. METHODS: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. RESULTS: CCT was the most heritable endophenotype in this cohort (h CONCLUSIONS: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedigree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.

14 Article Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma. 2017

Zhou, Tiger / Souzeau, Emmanuelle / Siggs, Owen M / Landers, John / Mills, Richard / Goldberg, Ivan / Healey, Paul R / Graham, Stuart / Hewitt, Alex W / Mackey, David A / Galanopoulos, Anna / Casson, Robert J / Ruddle, Jonathan B / Ellis, Jonathan / Leo, Paul / Brown, Matthew A / MacGregor, Stuart / Sharma, Shiwani / Burdon, Kathryn P / Craig, Jamie E. ·Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia. · University of Sydney Discipline of Ophthalmology, Sydney, Australia 3Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia. · University of Sydney Discipline of Ophthalmology, Sydney, Australia 4Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. · Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. · University of Tasmania Menzies Institute for Medical Research, Hobart, Australia. · University of Western Australia Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia. · University of Adelaide, Discipline of Ophthalmology & Visual Sciences, Adelaide, Australia. · Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. · University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia. · Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia. · Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia 6University of Tasmania Menzies Institute for Medical Research, Hobart, Australia. ·Invest Ophthalmol Vis Sci · Pubmed #28282485.

ABSTRACT: Purpose: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. Methods: The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Results: Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10-16). Conclusions: Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

15 Article Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma. 2017

Zhou, Tiger / Souzeau, Emmanuelle / Sharma, Shiwani / Landers, John / Mills, Richard / Goldberg, Ivan / Healey, Paul R / Graham, Stuart / Hewitt, Alex W / Mackey, David A / Galanopoulos, Anna / Casson, Robert J / Ruddle, Jonathan B / Ellis, Jonathan / Leo, Paul / Brown, Matthew A / MacGregor, Stuart / Lynn, David J / Burdon, Kathryn P / Craig, Jamie E. ·Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia. · University of Sydney Discipline of Ophthalmology, Sydney, Australia. · Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia. · Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. · University of Tasmania Menzies Institute for Medical Research, Hobart, Australia. · University of Western Australia Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia. · University of Adelaide, Discipline of Ophthalmology & Visual Sciences, Adelaide, Australia. · Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. · University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia. · Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia. · EMBL Australia Group, Infection & Immunity Theme, South Australian Medical and Health Research Institute, Adelaide, Australia. · Flinders University, School of Medicine, Adelaide, Australia. ·PLoS One · Pubmed #28264060.

ABSTRACT: PURPOSE: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants. METHODS: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB. RESULTS: POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG. CONCLUSION: This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.

16 Article New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. 2017

Springelkamp, Henriët / Iglesias, Adriana I / Mishra, Aniket / Höhn, René / Wojciechowski, Robert / Khawaja, Anthony P / Nag, Abhishek / Wang, Ya Xing / Wang, Jie Jin / Cuellar-Partida, Gabriel / Gibson, Jane / Bailey, Jessica N Cooke / Vithana, Eranga N / Gharahkhani, Puya / Boutin, Thibaud / Ramdas, Wishal D / Zeller, Tanja / Luben, Robert N / Yonova-Doing, Ekaterina / Viswanathan, Ananth C / Yazar, Seyhan / Cree, Angela J / Haines, Jonathan L / Koh, Jia Yu / Souzeau, Emmanuelle / Wilson, James F / Amin, Najaf / Müller, Christian / Venturini, Cristina / Kearns, Lisa S / Kang, Jae Hee / Anonymous11410892 / Tham, Yih Chung / Zhou, Tiger / van Leeuwen, Elisabeth M / Nickels, Stefan / Sanfilippo, Paul / Liao, Jiemin / van der Linde, Herma / Zhao, Wanting / van Koolwijk, Leonieke M E / Zheng, Li / Rivadeneira, Fernando / Baskaran, Mani / van der Lee, Sven J / Perera, Shamira / de Jong, Paulus T V M / Oostra, Ben A / Uitterlinden, André G / Fan, Qiao / Hofman, Albert / Tai, E-Shyong / Vingerling, Johannes R / Sim, Xueling / Wolfs, Roger C W / Teo, Yik Ying / Lemij, Hans G / Khor, Chiea Chuen / Willemsen, Rob / Lackner, Karl J / Aung, Tin / Jansonius, Nomdo M / Montgomery, Grant / Wild, Philipp S / Young, Terri L / Burdon, Kathryn P / Hysi, Pirro G / Pasquale, Louis R / Wong, Tien Yin / Klaver, Caroline C W / Hewitt, Alex W / Jonas, Jost B / Mitchell, Paul / Lotery, Andrew J / Foster, Paul J / Vitart, Veronique / Pfeiffer, Norbert / Craig, Jamie E / Mackey, David A / Hammond, Christopher J / Wiggs, Janey L / Cheng, Ching-Yu / van Duijn, Cornelia M / MacGregor, Stuart. ·Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands. · Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia. · Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, the Netherlands. · Department of Ophthalmology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland. · Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany. · Computational and Statistical Genomics Branch, National Human Genome Research Institute (NIH), Baltimore, MD, USA. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. · Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA. · NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China. · Beijing Ophthalmology and Visual Science Key Lab, Beijing, China. · Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. · Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK. · Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA. · Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. · Duke-National University of Singapore Graduate Medical School, Singapore, Singapore. · Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. · German Center for Cardiovascular Research (DZHK), Partner Site Hamburg, Luebeck, Kiel, Hamburg/Germany. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia. · Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. · Department of Ophthalmology, Flinders University, Adelaide, Australia. · Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Scotland, UK. · Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. · Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands. · Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands. · Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands. · The Netherlands Institute of Neuroscience KNAW, Amsterdam, the Netherlands. · Department of Medicine, National University of Singapore and National University Health System, Singapore, Singapore. · Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore. · Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore. · Glaucoma Service, The Rotterdam Eye Hospital, Rotterdam, the Netherlands. · Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore. · Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany. · Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. · Department of Molecular Epidemiology, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia. · Preventive Cardiology and Preventive Medicine/Center for Cardiology, University Medical Center Mainz, Mainz, Germany. · Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. · German Center for Cardiovascular Research (DZHK), partner site RhineMain, Mainz, Germany. · Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. · School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia. · Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA and. · Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany. ·Hum Mol Genet · Pubmed #28073927.

ABSTRACT: Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

17 Article Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals. 2017

Souzeau, Emmanuelle / Tram, Kien Hou / Witney, Martin / Ruddle, Jonathan B / Graham, Stuart L / Healey, Paul R / Goldberg, Ivan / Mackey, David A / Hewitt, Alex W / Burdon, Kathryn P / Craig, Jamie E. ·Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. · Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, Melbourne, Australia; and Ophthalmology, University of Melbourne, Department of Surgery, Melbourne, Australia. · Ophthalmology and Vision Science, Faculty of Medicine and Human Sciences, Macquarie University, Sydney, Australia; Discipline of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Sydney, Australia. · Discipline of Ophthalmology, Eye Associates, Sydney Eye Hospital, University of Sydney, Sydney, Australia. · Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Centre for Eye Research Australia, Royal Victorian Eye & Ear Hospital, Melbourne, Australia; and Ophthalmology, University of Melbourne, Department of Surgery, Melbourne, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia. Electronic address: jamie.craig@flinders.edu.au. ·Ophthalmology · Pubmed #27993484.

ABSTRACT: PURPOSE: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. MAIN OUTCOME MEASURES: Glaucoma clinical parameters and age at presentation. RESULTS: At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. CONCLUSIONS: Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

18 Article Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration. 2016

Cuellar-Partida, Gabriel / Craig, Jamie E / Burdon, Kathryn P / Wang, Jie Jin / Vote, Brendan J / Souzeau, Emmanuelle / McAllister, Ian L / Isaacs, Timothy / Lake, Stewart / Mackey, David A / Constable, Ian J / Mitchell, Paul / Hewitt, Alex W / MacGregor, Stuart. ·Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, 5001, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, 7001, Australia. · Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, 2145, Australia. · Launceston Eye Institute, Launceston, Tasmania, 7249, Australia. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, 6009, Australia. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, 3002, Australia. ·Sci Rep · Pubmed #27241461.

ABSTRACT: Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h(2)g = 0.42 ± 0.09) and AMD (h(2)g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h(2)g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

19 Article Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. 2016

Bailey, Jessica N Cooke / Loomis, Stephanie J / Kang, Jae H / Allingham, R Rand / Gharahkhani, Puya / Khor, Chiea Chuen / Burdon, Kathryn P / Aschard, Hugues / Chasman, Daniel I / Igo, Robert P / Hysi, Pirro G / Glastonbury, Craig A / Ashley-Koch, Allison / Brilliant, Murray / Brown, Andrew A / Budenz, Donald L / Buil, Alfonso / Cheng, Ching-Yu / Choi, Hyon / Christen, William G / Curhan, Gary / De Vivo, Immaculata / Fingert, John H / Foster, Paul J / Fuchs, Charles / Gaasterland, Douglas / Gaasterland, Terry / Hewitt, Alex W / Hu, Frank / Hunter, David J / Khawaja, Anthony P / Lee, Richard K / Li, Zheng / Lichter, Paul R / Mackey, David A / McGuffin, Peter / Mitchell, Paul / Moroi, Sayoko E / Perera, Shamira A / Pepper, Keating W / Qi, Qibin / Realini, Tony / Richards, Julia E / Ridker, Paul M / Rimm, Eric / Ritch, Robert / Ritchie, Marylyn / Schuman, Joel S / Scott, William K / Singh, Kuldev / Sit, Arthur J / Song, Yeunjoo E / Tamimi, Rulla M / Topouzis, Fotis / Viswanathan, Ananth C / Verma, Shefali Setia / Vollrath, Douglas / Wang, Jie Jin / Weisschuh, Nicole / Wissinger, Bernd / Wollstein, Gadi / Wong, Tien Y / Yaspan, Brian L / Zack, Donald J / Zhang, Kang / Study, Epic-Norfolk Eye / Anonymous3520854 / Weinreb, Robert N / Pericak-Vance, Margaret A / Small, Kerrin / Hammond, Christopher J / Aung, Tin / Liu, Yutao / Vithana, Eranga N / MacGregor, Stuart / Craig, Jamie E / Kraft, Peter / Howell, Gareth / Hauser, Michael A / Pasquale, Louis R / Haines, Jonathan L / Wiggs, Janey L. ·Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Division of Human Genetics, Genome Institute of Singapore, Singapore. · Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. · Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA. · Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. · Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, USA. · Singapore Eye Research Institute, Singapore National Eye Centre, Singapore. · Eye Academic Clinical Program, Duke-National University of Singapore Graduate Medical School, Singapore. · Section of Rheumatology and Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA. · Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa, USA. · Department of Anatomy and Cell Biology, University of Iowa, College of Medicine, Iowa City, Iowa, USA. · National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, London, UK. · Department of Ophthalmology, University College London, London, UK. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. · Eye Doctors of Washington, Chevy Chase, Maryland, USA. · Scripps Genome Center, University of California at San Diego, San Diego, California, USA. · Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia. · Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA. · Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia. · Medical Research Council Social Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK. · Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia. · Duke-National University of Singapore Graduate Medical School, Singapore. · The Jackson Laboratory, Bar Harbor, Maine, USA. · Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. · Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, West Virginia, USA. · Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA. · Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA. · Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA. · Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA. · Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, USA. · Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece. · Department of Genetics, Stanford University School of Medicine, Palo Alto, California, USA. · Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany. · Genentech, San Francisco, California, USA. · Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland, USA. · Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, San Diego, California, USA. · Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA. · James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, USA. ·Nat Genet · Pubmed #26752265.

ABSTRACT: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

20 Article TIMP1, TIMP2, and TIMP4 are increased in aqueous humor from primary open angle glaucoma patients. 2015

Ashworth Briggs, Esther L / Toh, Tze'Yo / Eri, Rajaraman / Hewitt, Alex W / Cook, Anthony L. ·School of Health Sciences, University of Tasmania, Australia. · Launceston Eye Institute and Launceston Eye Doctors, Tasmania, Australia. · School of Health Sciences, University of Tasmania, Australia ; Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia. ·Mol Vis · Pubmed #26539028.

ABSTRACT: PURPOSE: Elevated intraocular pressure (IOP) is the only known modifiable risk factor for primary open angle glaucoma (POAG), and it can be caused by reduced aqueous humor outflow from the anterior chamber. Outflow is predominantly regulated by the trabecular meshwork, consisting of specialized cells within a complex extracellular matrix (ECM). An imbalance between ECM-degrading matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) within the trabecular meshwork is thought to contribute to POAG. This study aimed to quantify levels of TIMPs and MMPs in aqueous humor samples from glaucomatous and non-glaucomatous eyes, analyze MMP/TIMP ratios, and correlate results with age, IOP, and Humphrey's visual field pattern standard deviation (PSD). METHODS: Aqueous humor samples were collected from 26 non-glaucomatous control subjects before cataract surgery and 23 POAG patients undergoing trabeculectomy or cataract surgery. Analyte concentrations were measured using multiplexed immunoassays. Statistical significance was assessed with Mann-Whitney U tests, and Spearman's method was used to assess correlations with age, IOP, and PSD. RESULTS: Concentrations of TIMP1 (p = 0.0008), TIMP2 (p = 0.002), TIMP4 (p = 0.002), and MMP2 (p = 0.020) were significantly increased in aqueous humor samples from POAG versus cataract samples. For the majority of MMP/TIMP molar ratios calculated for the cataract group, TIMPs outweighed MMPs. In POAG, molar ratios of MMP2/TIMP1 (p = 0.007) and MMP9/TIMP1 (p = 0.005) showed a significant decrease, corresponding to an elevated excess of TIMPs over MMPs in POAG compared to cataract samples. Conversely, MMP2/TIMP3 (p = 0.045) and MMP3/TIMP3 (p = 0.032) molar ratios increased. Several MMP/TIMP molar ratios correlated with IOP (r = 0.476-0.609, p = 0.007-0.034) and PSD (r = -0.482 to -0.655, p = 0.005-0.046) in POAG samples and with age in cataract control samples. CONCLUSIONS: An imbalance among MMPs and TIMPs was found in glaucomatous aqueous humor samples, with a shift toward raised TIMP levels. This may result in the inhibition of MMP activity, leading to an altered ECM composition in the TM and thereby contributing to increased outflow resistance.

21 Article Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy. 2015

Van Bergen, Nicole J / Crowston, Jonathan G / Craig, Jamie E / Burdon, Kathryn P / Kearns, Lisa S / Sharma, Shiwani / Hewitt, Alex W / Mackey, David A / Trounce, Ian A. ·Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. · Department of Ophthalmology, School of Medicine, Flinders University, Adelaide, Australia. · Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia; Lions Eye Institute, Perth, Australia. ·PLoS One · Pubmed #26496696.

ABSTRACT: Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function.

22 Article Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma. 2015

Gharahkhani, Puya / Burdon, Kathryn P / Hewitt, Alex W / Law, Matthew H / Souzeau, Emmanuelle / Montgomery, Grant W / Radford-Smith, Graham / Mackey, David A / Craig, Jamie E / MacGregor, Stuart. ·Queensland Institute of Medical Research Berghofer Medical Research Institute Brisbane, Queensland, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia 3Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia 4Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. · Queensland Institute of Medical Research Berghofer Medical Research Institute Brisbane, Queensland, Australia 5School of Medicine, University of Queensland, Herston Campus, Brisbane, Queensland, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia 6Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia 7South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. ·Invest Ophthalmol Vis Sci · Pubmed #26237198.

ABSTRACT: PURPOSE: Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. METHODS: A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. RESULTS: We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 × 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. CONCLUSIONS: We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays.

23 Article Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss. 2015

Souzeau, Emmanuelle / Hayes, Melanie / Zhou, Tiger / Siggs, Owen M / Ridge, Bronwyn / Awadalla, Mona S / Smith, James E H / Ruddle, Jonathan B / Elder, James E / Mackey, David A / Hewitt, Alex W / Healey, Paul R / Goldberg, Ivan / Morgan, William H / Landers, John / Dubowsky, Andrew / Burdon, Kathryn P / Craig, Jamie E. ·Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia. · SA Pathology, Flinders Medical Centre, Adelaide, Australia. · Department of Ophthalmology, Macquarie University, Royal North Shore Hospital, Sydney, Australia4Department of Ophthalmology, Children's Hospital at Westmead, Sydney, Australia. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. · Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia7Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia8Menzies Institute fo. · Centre for Vision Research, Department of Ophthalmology, Westmead Millennium Institute, University of Sydney, Sydney, Australia. · Discipline of Ophthalmology, University of Sydney and Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia. · Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia8Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. ·JAMA Ophthalmol · Pubmed #25950505.

ABSTRACT: IMPORTANCE: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. OBJECTIVE: To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. MAIN OUTCOMES AND MEASURES: Identification and characterization of CYP1B1 sequence variants. RESULTS: We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7.18; P = .008; ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. CONCLUSIONS AND RELEVANCE: Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.

24 Article A common variant near TGFBR3 is associated with primary open angle glaucoma. 2015

Li, Zheng / Allingham, R Rand / Nakano, Masakazu / Jia, Liyun / Chen, Yuhong / Ikeda, Yoko / Mani, Baskaran / Chen, Li-Jia / Kee, Changwon / Garway-Heath, David F / Sripriya, Sarangapani / Fuse, Nobuo / Abu-Amero, Khaled K / Huang, Chukai / Namburi, Prasanthi / Burdon, Kathryn / Perera, Shamira A / Gharahkhani, Puya / Lin, Ying / Ueno, Morio / Ozaki, Mineo / Mizoguchi, Takanori / Krishnadas, Subbiah Ramasamy / Osman, Essam A / Lee, Mei Chin / Chan, Anita S Y / Tajudin, Liza-Sharmini A / Do, Tan / Goncalves, Aurelien / Reynier, Pascal / Zhang, Hong / Bourne, Rupert / Goh, David / Broadway, David / Husain, Rahat / Negi, Anil K / Su, Daniel H / Ho, Ching-Lin / Blanco, Augusto Azuara / Leung, Christopher K S / Wong, Tina T / Yakub, Azhany / Liu, Yutao / Nongpiur, Monisha E / Han, Jong Chul / Hon, Do Nhu / Shantha, Balekudaru / Zhao, Bowen / Sang, Jinghong / Zhang, NiHong / Sato, Ryuichi / Yoshii, Kengo / Panda-Jonas, Songhomita / Ashley Koch, Allison E / Herndon, Leon W / Moroi, Sayoko E / Challa, Pratap / Foo, Jia Nee / Bei, Jin-Xin / Zeng, Yi-Xin / Simmons, Cameron P / Bich Chau, Tran Nguyen / Sharmila, Philomenadin Ferdinamarie / Chew, Merwyn / Lim, Blanche / Tam, Pansy O S / Chua, Elaine / Ng, Xiao Yu / Yong, Victor H K / Chong, Yaan Fun / Meah, Wee Yang / Vijayan, Saravanan / Seongsoo, Sohn / Xu, Wang / Teo, Yik Ying / Cooke Bailey, Jessica N / Kang, Jae H / Haines, Jonathan L / Cheng, Ching Yu / Saw, Seang-Mei / Tai, E-Shyong / Anonymous2611159 / Anonymous2621159 / Richards, Julia E / Ritch, Robert / Gaasterland, Douglas E / Pasquale, Louis R / Liu, Jianjun / Jonas, Jost B / Milea, Dan / George, Ronnie / Al-Obeidan, Saleh A / Mori, Kazuhiko / Macgregor, Stuart / Hewitt, Alex W / Girkin, Christopher A / Zhang, Mingzhi / Sundaresan, Periasamy / Vijaya, Lingam / Mackey, David A / Wong, Tien Yin / Craig, Jamie E / Sun, Xinghuai / Kinoshita, Shigeru / Wiggs, Janey L / Khor, Chiea-Chuen / Yang, Zhenglin / Pang, Chi Pui / Wang, Ningli / Hauser, Michael A / Tashiro, Kei / Aung, Tin / Vithana, Eranga N. ·Singapore Eye Research Institute, Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore. · Department of Ophthalmology, Duke University Eye Center, Durham, NC, USA. · Department of Genomic Medical Sciences. · Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China. · Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical School. · Department of Ophthalmology. · Singapore Eye Research Institute, Department of Ophthalmology, Yong Loo Lin School of Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore. · Department of Ophthalmology and Visual Sciences, The Chinese Uuniversity of Hong Kong Eye Hospital, Hong Kong, China. · Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Seoul Korea. · National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK. · SNONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India. · Department of Integrative Genomics, Tohoku Medical Megabank Organization, Sendai, Japan. · Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia, Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, FL, USA. · Chinese University of Hong Kong Joint Shantou International Eye Center, Shantou University, Shantou, China. · Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamilnadu, India. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia, Department of Ophthalmology, Flinders University, Adelaide, Australia. · Singapore Eye Research Institute, Duke-NUS Graduate Medical School, Singapore, Singapore, Singapore National Eye Center, Singapore, Singapore. · Department of Genetics and Computational Biology, Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. · Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. · Ozaki Eye Hospital, 1-15, Kamezaki, Hyuga, Miyazaki 883-0066, Japan. · Mizoguchi Eye Hospital, 6-13 Tawara-machi, Sasebo, Nagasaki 857-0016, Japan. · Glaucoma Services, Aravind Eye Hospital, Madurai, Tamilnadu, India. · Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. · Singapore Eye Research Institute. · Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore. · Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Kelantan, Malaysia. · Vietnam National Institute of Ophthalmology, Hanoi, Vietnam. · Ophthalmology Department. · Biochemistry Department, Angers University Hospital, Angers, France. · Department of Ophthalmology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. · Huntingdon Glaucoma Diagnostic & Research Centre, Hinchingbrooke Hospital, Huntingdon, UK. · Singapore National Eye Center, Singapore, Singapore. · Norfolk & Norwich University Hospital NHS Trust, Norwich, UK. · Heart of UK NHS Foundation Trust, Birmingham, UK. · School of Medicine, Dentistry and Biomedical Sciences, Centre for Experimental Medicine, Queen's University Belfast, Northern Ireland, UK. · Department of Medicine, Duke University Medical Center, Durham, NC, USA, Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia. · Medical Research Foundation, Sankara Nethralaya, Chennai, India. · Department of Medical Statistics, Kyoto Prefectural University of Medicine, Kyoto, Japan. · Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. · Department of Medicine, Duke University Medical Center, Durham, NC, USA. · Department of Ophthalmology and Visual Sciences. · Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore. · State Key Laboratory of Oncology in Southern China, Guangzhou, China, Department of Experimental Research, Sun Yat-Sen University Cancer Centre, Guangzhou, China. · Clinical Research Unit, Oxford University, 190 Ben Ham Tu, Ho Chi Minh City, Vietnam, Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford OX3 7LJ, UK. · Clinical Research Unit, Oxford University, 190 Ben Ham Tu, Ho Chi Minh City, Vietnam. · Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. · Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. · Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. · Singapore Eye Research Institute, Department of Ophthalmology, Yong Loo Lin School of Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore, Singapore National Eye Center, Singapore, Singapore. · Singapore Eye Research Institute, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. · Department of Medicine, National University Health System & National University of Singapore, Singapore. · Department of Ophthalmology and Visual Sciences, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. · Einhorn Clinical Research Center, Department of Ophthalmology, New York Eye and Ear Infirmary, New York, NY, USA. · Eye Doctors of Washington DC, Washington, DC, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia, Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia. · Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL, USA. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia, Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, WA, Australia. · Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore, Department of Ophthalmology, Yong Loo Lin School of Medicine. · Department of Ophthalmology, Flinders University, Adelaide, Australia. · Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical School, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, China, Myopia Key Laboratory of the Ministry of Health of China, Shanghai, China and. · Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore, Department of Ophthalmology, Yong Loo Lin School of Medicine, eranga.n.v@sericom.sg khorcc@gis.a-star.edu.sg. · Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China, Chinese Academy of Sciences, Sichuan Translational Medicine Hospital, Chengdu, China. · Department of Ophthalmology, Duke University Eye Center, Durham, NC, USA, Department of Medicine, Duke University Medical Center, Durham, NC, USA. · Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore, Department of Ophthalmology, Yong Loo Lin School of Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore. · Singapore Eye Research Institute, Department of Ophthalmology, Yong Loo Lin School of Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore, eranga.n.v@sericom.sg khorcc@gis.a-star.edu.sg. ·Hum Mol Genet · Pubmed #25861811.

ABSTRACT: Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

25 Article A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. 2015

Aung, Tin / Ozaki, Mineo / Mizoguchi, Takanori / Allingham, R Rand / Li, Zheng / Haripriya, Aravind / Nakano, Satoko / Uebe, Steffen / Harder, Jeffrey M / Chan, Anita S Y / Lee, Mei Chin / Burdon, Kathryn P / Astakhov, Yury S / Abu-Amero, Khaled K / Zenteno, Juan C / Nilgün, Yildirim / Zarnowski, Tomasz / Pakravan, Mohammad / Safieh, Leen Abu / Jia, Liyun / Wang, Ya Xing / Williams, Susan / Paoli, Daniela / Schlottmann, Patricio G / Huang, Lulin / Sim, Kar Seng / Foo, Jia Nee / Nakano, Masakazu / Ikeda, Yoko / Kumar, Rajesh S / Ueno, Morio / Manabe, Shin-ichi / Hayashi, Ken / Kazama, Shigeyasu / Ideta, Ryuichi / Mori, Yosai / Miyata, Kazunori / Sugiyama, Kazuhisa / Higashide, Tomomi / Chihara, Etsuo / Inoue, Kenji / Ishiko, Satoshi / Yoshida, Akitoshi / Yanagi, Masahide / Kiuchi, Yoshiaki / Aihara, Makoto / Ohashi, Tsutomu / Sakurai, Toshiya / Sugimoto, Takako / Chuman, Hideki / Matsuda, Fumihiko / Yamashiro, Kenji / Gotoh, Norimoto / Miyake, Masahiro / Astakhov, Sergei Y / Osman, Essam A / Al-Obeidan, Saleh A / Owaidhah, Ohoud / Al-Jasim, Leyla / Al Shahwan, Sami / Fogarty, Rhys A / Leo, Paul / Yetkin, Yaz / Oğuz, Çilingir / Kanavi, Mozhgan Rezaei / Beni, Afsaneh Nederi / Yazdani, Shahin / Akopov, Evgeny L / Toh, Kai-Yee / Howell, Gareth R / Orr, Andrew C / Goh, Yufen / Meah, Wee Yang / Peh, Su Qin / Kosior-Jarecka, Ewa / Lukasik, Urszula / Krumbiegel, Mandy / Vithana, Eranga N / Wong, Tien Yin / Liu, Yutao / Koch, Allison E Ashley / Challa, Pratap / Rautenbach, Robyn M / Mackey, David A / Hewitt, Alex W / Mitchell, Paul / Wang, Jie Jin / Ziskind, Ari / Carmichael, Trevor / Ramakrishnan, Rangappa / Narendran, Kalpana / Venkatesh, Rangaraj / Vijayan, Saravanan / Zhao, Peiquan / Chen, Xueyi / Guadarrama-Vallejo, Dalia / Cheng, Ching Yu / Perera, Shamira A / Husain, Rahat / Ho, Su-Ling / Welge-Luessen, Ulrich-Christoph / Mardin, Christian / Schloetzer-Schrehardt, Ursula / Hillmer, Axel M / Herms, Stefan / Moebus, Susanne / Nöthen, Markus M / Weisschuh, Nicole / Shetty, Rohit / Ghosh, Arkasubhra / Teo, Yik Ying / Brown, Matthew A / Lischinsky, Ignacio / Anonymous5830821 / Anonymous5840821 / Crowston, Jonathan G / Coote, Michael / Zhao, Bowen / Sang, Jinghong / Zhang, Nihong / You, Qisheng / Vysochinskaya, Vera / Founti, Panayiota / Chatzikyriakidou, Anthoula / Lambropoulos, Alexandros / Anastasopoulos, Eleftherios / Coleman, Anne L / Wilson, M Roy / Rhee, Douglas J / Kang, Jae Hee / May-Bolchakova, Inna / Heegaard, Steffen / Mori, Kazuhiko / Alward, Wallace L M / Jonas, Jost B / Xu, Liang / Liebmann, Jeffrey M / Chowbay, Balram / Schaeffeler, Elke / Schwab, Matthias / Lerner, Fabian / Wang, Ningli / Yang, Zhenglin / Frezzotti, Paolo / Kinoshita, Shigeru / Fingert, John H / Inatani, Masaru / Tashiro, Kei / Reis, André / Edward, Deepak P / Pasquale, Louis R / Kubota, Toshiaki / Wiggs, Janey L / Pasutto, Francesca / Topouzis, Fotis / Dubina, Michael / Craig, Jamie E / Yoshimura, Nagahisa / Sundaresan, Periasamy / John, Simon W M / Ritch, Robert / Hauser, Michael A / Khor, Chiea-Chuen. ·1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [4] Division of Human Genetics, Genome Institute of Singapore, Singapore. [5] Duke University-National University of Singapore Graduate Medical School, Singapore. · 1] Ozaki Eye Hospital, Hyuga, Japan. [2] Hayashi Eye Hospital, Fukuoka, Japan. · Mizoguchi Eye Hospital, Sasebo, Japan. · Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. · Division of Human Genetics, Genome Institute of Singapore, Singapore. · Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India. · Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan. · Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany. · Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USA. · 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. · Singapore Eye Research Institute, Singapore. · 1] Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. [2] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. · Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia. · 1] Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. [2] Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA. · 1] Department of Genetics, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico. [2] Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico. · Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Turkey. · Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland. · Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. · King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. · Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China. · Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China. · Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa. · Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy. · Organización Médica de Investigación, Buenos Aires, Argentina. · 1] Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China. [2] School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [3] Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China. · Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan. · Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. · Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, India. · Hayashi Eye Hospital, Fukuoka, Japan. · Shinjo Eye Clinic, Miyazaki, Japan. · Ideta Eye Hospital, Kumamoto, Japan. · Miyata Eye Hospital, Miyazaki, Japan. · 1] Miyata Eye Hospital, Miyazaki, Japan. [2] Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. · Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. · Sensho-kai Eye Institute, Kyoto, Japan. · Inouye Eye Hospital, Tokyo, Japan. · Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan. · Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan. · Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, Japan. · Yotsuya Shirato Eye Clinic, Tokyo, Japan. · Ohashi Eye Center, Sapporo, Japan. · Tane Memorial Eye Hospital, Osaka, Japan. · Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. · Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · 1] Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan. [2] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. · Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. · University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. · 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. · Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa. · Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia. · 1] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. [2] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. · Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia. · Department of Genetics, Aravind Medical Research Foundation, Madurai, India. · Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China. · Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang Uygur Autonomous Region, China. · 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. · National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore. · Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany. · Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore. · 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland. · Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. · 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. · Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany. · 1] Singapore Eye Research Institute, Singapore. [2] Genes, Repair and Regeneration in Ophthalmic Workstation Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India. · 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore. · Centro Oftalmológico Lischinsky, Tucumán, Argentina. · 1] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. [2] Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia. · St. Petersburg Academic University, St. Petersburg, Russia. · Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, American Hellenic Educational Progressive Association Hospital, Thessaloniki, Greece. · Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. · Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA. · Wayne State University, Detroit, Michigan, USA. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. · Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Ophthalmology, Military Hospital Begin, Paris, France. · 1] Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark. [2] Department of Ophthalmology, Glostrup University Hospital, Glostrup, Denmark. · 1] Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA. [2] Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. · Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, Germany. · New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USA. · Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, Singapore. · Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. · 1] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. [2] Department of Clinical Pharmacology, University Hospital, Tübingen, Germany. [3] German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. · Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina. · Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy. · Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan. · 1] King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. [2] Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · 1] Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · 1] Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia. [2] St. Petersburg Academic University, St. Petersburg, Russia. · Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA. · 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. · 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [3] Division of Human Genetics, Genome Institute of Singapore, Singapore. ·Nat Genet · Pubmed #25706626.

ABSTRACT: Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

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