TY - JOUR
T1 - Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
AU - Iglesias, Adriana I.
AU - Mishra, Aniket
AU - Vitart, Veronique
AU - Bykhovskaya, Yelena
AU - Höhn, René
AU - Springelkamp, Henriët
AU - Cuellar-Partida, Gabriel
AU - Gharahkhani, Puya
AU - Bailey, Jessica N. Cooke
AU - Willoughby, Colin E.
AU - Li, Xiaohui
AU - Yazar, Seyhan
AU - Nag, Abhishek
AU - Khawaja, Anthony P.
AU - Polašek, Ozren
AU - Siscovick, David
AU - Mitchell, Paul
AU - Chung Tham, Yih
AU - Haines, Jonathan L.
AU - Kearns, Lisa S.
AU - Hayward, Caroline
AU - Shi, Yuan
AU - van Leeuwen, Elisabeth M.
AU - Taylor, Kent D.
AU - Blue Mountains Eye Study—GWAS group
AU - Bonnemaijer, Pieter
AU - Rotter, Jerome I.
AU - Martin, Nicholas G.
AU - Zeller, Tanja
AU - Mills, Richard A.
AU - Souzeau, Emmanuelle
AU - Staffieri, Sandra E.
AU - Jonas, Jost B.
AU - Schmidtmann, Irene
AU - Boutin, Thibaud
AU - Kang, Jae H.
AU - Lucas, Sionne E. M.
AU - Wong, Tien Yin
AU - Beutel, Manfred E.
AU - Wilson, James F.
AU - NEIGHBORHOOD Consortium
AU - Wellcome Trust Case Control Consortium 2 (WTCCC2)
AU - Uitterlinden, André G.
AU - Vithana, Eranga N.
AU - Foster, Paul J.
AU - Hysi, Pirro G.
AU - Hewitt, Alex W.
AU - Khor, Chiea Chuen
AU - Pasquale, Louis R.
AU - Montgomery, Grant W.
AU - Klaver, Caroline C. W.
AU - Aung, Tin
AU - Pfeiffer, Norbet
AU - Mackey, David A.
AU - Hammond, Christopher J.
AU - Cheng, Ching-Yu
AU - Craig, Jamie E.
AU - Rabinowitz, Yaron S.
AU - Wiggs, Janey L.
AU - Burdon, Kathryn P.
AU - van Duijn, Cornelia M.
AU - MacGregor, Stuart
PY - 2018/5/14
Y1 - 2018/5/14
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-018-03646-6
DO - 10.1038/s41467-018-03646-6
M3 - Article
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
M1 - 1864
ER -