Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Authors: 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. ,   Blue Mountains Eye Study—GWAS group, Wang Jie Jin , Rochtchina Elena , Attia John , Scott Rodney , Holliday Elizabeth G. , Wong Tien Yin , Baird Paul N. , Xie Jing , Inouye Michael , Viswanathan Ananth , Sim Xueling , 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. ,   NEIGHBORHOOD Consortium, Allingham R. Rand , Brilliant Murray H. , Budenz Donald L. , Christen William G. , Fingert John , Friedman David S. , Gaasterland Douglas , Gaasterland Terry , Hauser Michael A. , Kraft Peter , Lee Richard K. , Lichter Paul R. , Liu Yutao , Loomis Stephanie J. , Moroi Sayoko E. , Pericak-Vance Margaret A. , Realini Anthony , Richards Julia E. , Schuman Joel S. , Scott William K. , Singh Kuldev , Sit Arthur J. , Vollrath Douglas , Weinreb Robert N. , Wollstein Gadi , Zack Donald J. , Zhang Kang ,   Wellcome Trust Case Control Consortium 2 (WTCCC2), Donnelly Peter , Barroso Ines , Blackwell Jenefer M. , Bramon Elvira , Brown Matthew A. , Casas Juan P. , Corvin Aiden , Deloukas Panos , Duncanson Audrey , Jankowski Janusz , Markus Hugh S. , Mathew Christopher G. , Palmer Colin N. A. , Plomin Robert , Rautanen Anna , Sawcer Stephen J. , Trembath Richard C. , Wood Nicholas W. , Spencer Chris C. A. , Band Gavin , Bellenguez Céline , Freeman Colin , Hellenthal Garrett , Giannoulatou Eleni , Pirinen Matti , Pearson Richard , Strange Amy , Su Zhan , Vukcevic Damjan , Langford Cordelia , Hunt Sarah E. , Edkins Sarah , Gwilliam Rhian , Blackburn Hannah , Bumpstead Suzannah J. , Dronov Serge , Gillman Matthew , Gray Emma , Hammond Naomi , Jayakumar Alagurevathi , McCann Owen T. , Liddle Jennifer , Potter Simon C. , Ravindrarajah Radhi , Ricketts Michelle , Waller Matthew , Weston Paul , Widaa Sara , Whittaker Pamela , 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 
Published: May 2018

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.