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Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.
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; Polasek, 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; 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; 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.
Afiliación
  • Iglesias AI; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Mishra A; Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Vitart V; Department of Clinical Genetics, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Bykhovskaya Y; University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, F-33000, Bordeaux, France.
  • Höhn R; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.
  • Springelkamp H; Regenerative Medicine Institute and Department of Surgery, Cedars-Sinai Medical Center, CA 90048, Los Angeles, CA, USA.
  • Cuellar-Partida G; Cornea Genetic Eye Institute, CA 90048, Los Angeles, CA, USA.
  • Gharahkhani P; Department of Ophthalmology, University Medical Center Mainz, 55131, Mainz, Germany.
  • Bailey JNC; Department of Ophthalmology, Inselspital, University Hospital Bern, University of Bern, Bern, CH-3010, Switzerland.
  • Willoughby CE; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Li X; Statistical Genetics, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia.
  • Yazar S; Statistical Genetics, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia.
  • Nag A; Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH 44106, Cleveland, OH, USA.
  • Khawaja AP; Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Polasek O; Biomedical Sciences Research Institute, Ulster University, BT52 1SA, Belfast, Northern Ireland, UK.
  • Siscovick D; Royal Victoria Hospital, Belfast Health and Social Care Trust, BT12 6BA, Belfast, Northern Ireland, UK.
  • Mitchell P; 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.
  • Tham YC; Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, CA, USA.
  • Haines JL; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.
  • Kearns LS; Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, WA 6009, Perth, WA, Australia.
  • Hayward C; Department of Twin Research and Genetic Epidemiology, King's College London, WC2R 2LS, London, UK.
  • Shi Y; Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, CB2 0SR, Cambridge, UK.
  • van Leeuwen EM; NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, EC1V 9EL, London, UK.
  • Taylor KD; Faculty of Medicine, University of Split, HR-21000, Split, Croatia.
  • Bonnemaijer P; The New York Academy of Medicine, NY 10029, New York, NY, USA.
  • Rotter JI; Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, NSW 2145, Sydney, NSW, Australia.
  • Martin NG; Singapore Eye Research Institute, Singapore National Eye Centre, 168751, Singapore, Singapore.
  • Zeller T; Department of Population and Quantitative Health Sciences, Case Western Reserve University, OH 44106, Cleveland, OH, USA.
  • Mills RA; Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Souzeau E; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, VIC 3002, East Melbourne, Australia.
  • Staffieri SE; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.
  • Jonas JB; Singapore Eye Research Institute, Singapore National Eye Centre, 168751, Singapore, Singapore.
  • Schmidtmann I; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Boutin T; 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.
  • Kang JH; Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, CA, USA.
  • Wong TY; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.
  • Beutel ME; 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.
  • Wilson JF; Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, CA, USA.
  • Uitterlinden AG; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, 20246, Hamburg, Germany.
  • Vithana EN; Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.
  • Foster PJ; Department of Ophthalmology, Flinders University, SA 5042, Adelaide, Australia.
  • Hysi PG; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, VIC 3002, East Melbourne, Australia.
  • Hewitt AW; Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, 68167, Mannheim, Germany.
  • Khor CC; Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, 55131, Mainz, Germany.
  • Pasquale LR; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.
  • Montgomery GW; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, MA, USA.
  • Klaver CCW; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, TAS, Australia.
  • Aung T; Singapore Eye Research Institute, Singapore National Eye Centre, 168751, Singapore, Singapore.
  • Pfeiffer N; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, 169857, Singapore, Singapore.
Nat Commun ; 9(1): 1864, 2018 05 14.
Article en En | MEDLINE | ID: mdl-29760442
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 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Asunto(s)
Córnea/metabolismo; Genoma Humano; Glaucoma de Ángulo Abierto/genética; Queratocono/genética; Polimorfismo de Nucleótido Simple; Carácter Cuantitativo Heredable; Proteínas ADAMTS/genética; Proteínas ADAMTS/metabolismo; Pueblo Asiatico; Córnea/anomalías; Córnea/patología; Enfermedades de la Córnea/etnología; Enfermedades de la Córnea/genética; Enfermedades de la Córnea/metabolismo; Enfermedades de la Córnea/patología; Distrofias Hereditarias de la Córnea/etnología; Distrofias Hereditarias de la Córnea/genética; Distrofias Hereditarias de la Córnea/metabolismo; Distrofias Hereditarias de la Córnea/patología; Decorina/genética; Decorina/metabolismo; Síndrome de Ehlers-Danlos/etnología; Síndrome de Ehlers-Danlos/genética; Síndrome de Ehlers-Danlos/metabolismo; Síndrome de Ehlers-Danlos/patología; Enfermedades Hereditarias del Ojo/etnología; Enfermedades Hereditarias del Ojo/genética; Enfermedades Hereditarias del Ojo/metabolismo; Enfermedades Hereditarias del Ojo/patología; Fibrilina-1/genética; Fibrilina-1/metabolismo; Expresión Génica; Estudio de Asociación del Genoma Completo; Glaucoma de Ángulo Abierto/etnología; Glaucoma de Ángulo Abierto/metabolismo; Glaucoma de Ángulo Abierto/patología; Humanos; Queratocono/etnología; Queratocono/metabolismo; Queratocono/patología; Síndrome de Loeys-Dietz/etnología; Síndrome de Loeys-Dietz/genética; Síndrome de Loeys-Dietz/metabolismo; Síndrome de Loeys-Dietz/patología; Lumican/genética; Lumican/metabolismo; Síndrome de Marfan/etnología; Síndrome de Marfan/genética; Síndrome de Marfan/metabolismo; Síndrome de Marfan/patología; Análisis de la Aleatorización Mendeliana; Miopía/etnología; Miopía/genética; Miopía/metabolismo; Miopía/patología; Proteoglicanos/genética
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genoma Humano / Glaucoma de Ángulo Abierto / Córnea / Carácter Cuantitativo Heredable / Polimorfismo de Nucleótido Simple / Queratocono Tipo de estudio: Prognostic_studies / Risk_factors_studies / Systematic_reviews Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genoma Humano / Glaucoma de Ángulo Abierto / Córnea / Carácter Cuantitativo Heredable / Polimorfismo de Nucleótido Simple / Queratocono Tipo de estudio: Prognostic_studies / Risk_factors_studies / Systematic_reviews Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos