학술논문
Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
Document Type
Journal Article
Author
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.; 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.; Staffieri, Sandra E.; Jonas, Jost B.; Schmidtmann, Irene; Boutin, Thibaud; Kang, Jae H.; Lucas, Sionne E. M.; Beutel, Manfred E.; Wilson, James F.; 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; 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
Source
Iglesias, A. I., A. Mishra, V. Vitart, Y. Bykhovskaya, R. Höhn, H. Springelkamp, G. Cuellar-Partida, et al. 2018. “Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.” Nature Communications 9 (1): 1864. doi:10.1038/s41467-018-03646-6. http://dx.doi.org/10.1038/s41467-018-03646-6.
Subject
Language
English
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 × 10−5) 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.