机构：[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]Ozaki Eye Hospital, Hyuga, Miyazaki, Japan[5]Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan[6]Academic Clinical Program for Ophthalmology and Visual Sciences, Office of Clinical and Academic Faculty Affairs, Duke–NUS Graduate Medical School, Singapore[7]Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany[8]deCODE Genetics, Reykjavik, Iceland[9]Mizoguchi Eye Hospital, Sasebo, Japan[10]Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA[11]Aravind Eye Hospital, Madurai, India[12]Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa[13]Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St.Petersburg, Russia[14]Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada[15]Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada[16]Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia[17]Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia[18]Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan[19]Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan[20]Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia[21]Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA[22]Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA[23]Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA[24]Genome Institute of Singapore, Singapore[25]Department of Genetics, Aravind Medical Research Foundation, Madurai, India[26]‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania[27]Department of Ophthalmology, University Emergency Hospital, Bucharest, Romania[28]Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA[29]Department of Biostatistics, University of Washington, Seattle, Washington, USA[30]Hayashi Eye Hospital, Fukuoka, Japan[31]Shinjo Eye Clinic, Miyazaki, Japan[32]Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland[33]Inoue Eye Hospital, Tokyo, Japan[34]Department of Ophthalmology, Hacettepe University, Faculty of Medicine, Ankara, Turkey[35]Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain[36]Fernández-Vega Ophthalmological Institute, Oviedo, Spain[37]Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, USA[38]Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan[39]Department of Medical Genetics, University of Helsinki, Helsinki, Finland[40]Organización Médica de Investigación, Buenos Aires, Argentina[41]Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina[42]Clinique Spécialisée en Ophtalmologie Mohammedia, Mohammedia, Morocco[43]Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey[44]Ufa Eye Research Institute, Ufa, Russia[45]Department of Ophthalmology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea[46]Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Republic of Korea[47]Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan[48]Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Japan[49]Genetics Department, Institute of Ophthalmology ‘Conde de Valenciana’, Mexico City, Mexico[50]Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico.[51]Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University of Heidelberg, Mannheim, Germany[52]Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China首都医科大学附属同仁医院[53]Narayana Nethralaya Eye Hospital, Bangalore, India[54]Chichua Medical Center Mzera, LLC, Tbilisi, Georgia[55]Jadhavbhai Nathamal Singhvi Department of Glaucoma, Medical Research Foundation, Chennai, India[56]Vietnam National Institute of Ophthalmology, Hanoi, Vietnam[57]King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia[58]Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA[59]Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain[60]Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain[61]Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran[62]Farabi Eye Hospital, Tehran University Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran[63]Ideta Eye Hospital, Kumamoto City, Japan[64]Eye Clinic, Rigshospitalet–Glostrup, Glostrup, Denmark[65]John A.Moran Eye Center, Department of Ophthalmology, University of Utah, Salt Lake City, Utah, USA[66]Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[67]School of Medicine, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[68]Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, China[69]Center for Human Molecular Biology and Genetics, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China四川省人民医院[70]Sichuan Translational Research Hospital, Chinese Academy of Sciences, Chengdu, China[71]Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China首都医科大学附属同仁医院[72]Shenzhen Key Laboratory of Ophthalmology, Shenzhen Eye Hospital, Jinan University, Shenzhen, China[73]Département d’Ophtalmologie, Centre Hospitalier Universitaire, Angers, France[74]Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France[75]David Tvildiani Medical University, Tbilisi, Georgia[76]Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany[77]Department of Ophthalmology, Medical University Graz, Graz, Austria[78]Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany[79]Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece[80]Laboratory of General Biology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece[81]GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India[82]Santa Lucia Eye Hospital from Buenos Aires, Buenos Aires, Argentina[83]Aravind Eye Hospital, Pondicherry, India[84]Aravind Eye Hospital, Tirunelveli, India[85]Aravind Eye Hospital, Coimbatore, India[86]Vision Research Foundation, Chennai, India[87]Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran[88]Dipartimento di Scienze Chirurgiche, Università di Torino, Turin, Italy[89]Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy[90]Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy[91]Department of Health Sciences, University of Milan, Milan, Italy[92]Department of Nephrology, University Vita-Salute San Raffaele, Milan, Italy[93]Miyata Eye Hospital, Miyazaki, Japan[94]Sensho-kai Eye Institute, Kyoto, Japan[95]Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan[96]Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan[97]Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan[98]Ohashi Eye Center, Sapporo, Japan[99]Tane Memorial Eye Hospital, Osaka, Japan[100]Department of Ophthalmology, University of Tokyo, Tokyo, Japan[101]Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan[102]Center for Genomic Medicine, INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan[103]Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan[104]Department of Ophthalmology, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea[105]Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea[106]Laboratoires RAFEI, Mohammedia, Morocco[107]Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands[108]Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria[109]Department of Ophthalmology, University College Hospital, Ibadan, Nigeria[110]ECWA Eye Hospital, Kano, Nigeria[111]Department of Ophthalmology, University of Lagos, Lagos, Nigeria[112]Guinness Eye Centre, Lagos University Teaching Hospital, Lagos, Nigeria[113]Department of Ophthalmology, ESUT Teaching Hospital Parklane, Enugu, Nigeria[114]Eye Specialists Hospital, Enugu, Nigeria[115]Department of Ophthalmology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand[116]Department of Ophthalmology, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria[117]Department of Ophthalmology, College of Medicine, University of Nigeria, Nsukka, Ituku Ozalla Campus, Enugu, Nigeria[118]Department of Environmental Sciences, COMSATS Institute of Information Technology, Abbottabad, Pakistan[119]Pakistan Institute of Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan[120]Centro Oftalmologico Lischinsky, Tucumán, Argentina[121]Universidad Peruana Cayetano Heredia, Hospital Nacional Arzobispo Loayza, Lima, Peru[122]Instituto de Glaucoma y Catarata, Lima, Peru[123]Clinical Research Centre Adolphe de Rothschild, Société Médicale de Beaulieu, Geneva, Switzerland[124]Mater Misericordiae University Hospital, Dublin, Ireland[125]Shri Mithu Tulsi, LV Prasad Eye Institute, Bhubaneswar, India[126]Hospital Córdoba, Córdoba, Argentina[127]Centro Oftalmologico Charles, Buenos Aires, Argentina[128]Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia[129]Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia[130]St.Petersburg Academic University, St.Petersburg, Russia[131]Clinical Pharmacology, SingHealth, Singapore[132]Clinical Pharmacology Laboratory, National Cancer Centre, Singapore[133]Office of Clinical Sciences, Duke–NUS Medical School, Singapore[134]Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore[135]Department of Ophthalmology, Tan Tock Seng Hospital, Singapore[136]Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain[137]Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain[138]GENVIP Research Group, Instituto de Investigación Sanitaria de Santiago, Santiago de Compostela, Spain[139]Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain[140]Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain[141]Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand[142]Department of Ophthalmology, Rajavithi Hospital, Bangkok, Thailand[143]Department of Ophthalmology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand[144]Institut Pasteur, Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Paris, France[145]Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Paris, France[146]Department of General Pediatrics, Medical University of Graz, Graz, Austria[147]Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK[148]Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany[149]Department of Biomedicine, University of Basel, Basel, Switzerland[150]Division of Medical Genetics, University Hospital Basel, Basel, Switzerland[151]Institute of Human Genetics, University of Bonn, Bonn, Germany[152]Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany[153]Division of Ophthalmology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa[154]Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa[155]Department of Genetics, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey[156]Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey[157]DAMAGEN Genetic Diagnostic Center, Ankara, Turkey[158]School of Medicine, Wayne State University, Detroit, Michigan, USA[159]Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA[160]Department of Cellular Biology and Anatomy, Center for Biotechnology and Genomic Medicine, James and Jean Culver Discovery Institute, Augusta University, Augusta, Georgia, USA[161]Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA[162]Hamilton Glaucoma Center, Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, San Diego, California, USA[163]Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan[164]Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan[165]Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands[166]Department of Ophthalmology, University of Turku and Turku University Hospital, Turku, Finland[167]Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA[168]Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA[169]Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA[170]Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA[171]Ophthalmic Consultants of Boston, Boston, Massachusetts, USA[172]Institute of Biomedical Technologies, Italian National Research Centre (ITB-CNR), Segrate-Milano, Italy[173]Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan[174]Department of Biochemistry, Al-Nafees Medical College and Hospital, Isra University, Islamabad, Pakistan[175]Department of Epidemiology, Harvard T.H.Chan School of Public Health, Boston, Massachusetts, USA[176]John P.Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA[177]Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA[178]Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA[179]Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA[180]Institute of Inflammation and Repair, University of Manchester, Manchester, UK[181]Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden[182]Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark[183]Department of Pathology, Rigshospitalet, Eye Pathology Section, University of Copenhagen, Copenhagen, Denmark[184]Department of Ophthalmology,University of Helsinki and Helsinki University Hospital, Helsinki, Finland.[185]Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA[186]Institute of Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA[187]Faculty of Medicine, University of Iceland, Reykjavik, Iceland[188]Department of Ophthalmology, Landspitali University Hospital, Reykjavik, Iceland[189]Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA[190]Dr.G.Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, Aravind Eye Hospital, Madurai, India[191]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
基金：
This research is supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore (to C.C.K.), by the Glaucoma Foundation of New York (to C.C.K.), by grants from the National Medical Research Council, Singapore NMRC/TCR/008-SERI/2013 and NMRC/STAR/0023/2014 to T.A. and NMRC/CBRG/0032/2013 to E.N.V.), by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF-E23) from Germany to F.P. and U.S.-S., and by grants from the US National Institutes of Health: UM1 CA186107, R01 CA49449, R01 AR056291, R01 CA131332, P01 CA055075, R01 CA134958 and R01 EY015473 to J.L.W. For XFS cases in the US GWAS data set, genotyping services were provided through a grant to J.L.W. (HG008597) by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to The Johns Hopkins University, contract HHSN268201200008I. The Beijing, China, collection was supported by funding from the National Natural Science Foundation of China (81030016 and 81570837), the Program of Beijing Scholars (2013), the National Major Scientific and Technological Special Project for Significant New Drugs Development (2011ZX09302-007-05) and Leading Talents-High-Level Talents of the Health System of Beijing (2009-1-05) to N. Wang.
第一作者机构：[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
共同第一作者：
通讯作者：
通讯机构：[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[24]Genome Institute of Singapore, Singapore[191]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
推荐引用方式(GB/T 7714)：
Tin Aung,Mineo Ozaki,Mei Chin Lee,et al.Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci[J].NATURE GENETICS.2017,49(7):993-+.doi:10.1038/ng.3875.
APA：
Tin Aung,Mineo Ozaki,Mei Chin Lee,Ursula Schlötzer-Schrehardt,Gudmar Thorleifsson...&Chiea Chuen Khor.(2017).Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.NATURE GENETICS,49,(7)
MLA：
Tin Aung,et al."Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci".NATURE GENETICS 49..7(2017):993-+
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