학술논문
Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.
Document Type
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; Blue Mountains Eye Study—GWAS group; 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 EM; Wong, Tien Yin; Beutel, Manfred E; Wilson, James F; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); 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 CW; 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
Nature communications. 9(1)
Subject
Language
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.