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

Adriana I Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N Cooke Bailey, Colin E Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P Khawaja, Ozren Polašek, David Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L Haines, Lisa S Kearns, Caroline Hayward, Yuan Shi, Elisabeth M van Leeuwen, Kent D Taylor, Pieter Bonnemaijer, Jerome I Rotter, Nicholas G Martin, Tanja Zeller, Richard A Mills, Emmanuelle Souzeau, Sandra E Staffieri, Jost B Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H Kang, Sionne E M Lucas, Tien Yin Wong, Manfred E Beutel, James F Wilson, André G Uitterlinden, Eranga N Vithana, Paul J Foster, Pirro G Hysi, Alex W Hewitt, Chiea Chuen Khor, Louis R Pasquale, Grant W Montgomery, Caroline C W Klaver, Tin Aung, Norbert Pfeiffer, David A Mackey, Christopher J Hammond, Ching-Yu Cheng, Jamie E Craig, Yaron S Rabinowitz, Janey L Wiggs, Kathryn P Burdon, Cornelia M van Duijn, Stuart MacGregor

Journal: Nature communications 2018;9(1):1864

PMID: 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) 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.

Address: 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.; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.; 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.; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.; 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.; Singapore Eye Research Institute, Singapore National Eye Centre, 168751, Singapore, Singapore.; 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.; Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, EH42XU, Edinburgh, UK.; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, EH16 4UX, Edinburgh, UK.; Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.; 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.; NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, EC1V 9EL, London, UK.; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, VIC 3002, East Melbourne, Australia.; 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.; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, MA, USA.; Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, MA, USA.; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia.; Institute for Molecular Bioscience, University of Queensland, QLD 4067, Brisbane, Australia.; Department of Ophthalmology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.; Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.; Department of Ophthalmology, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.; Department of Ophthalmology, University Medical Center Mainz, 55131, Mainz, Germany.; Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, WA 6009, Perth, WA, Australia.; Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, MA, USA.; Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands.; Statistical Genetics, QIMR Berghofer Medical Research Institute, QLD 4029, Brisbane, Australia. [email protected].
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