TY - JOUR
T1 - Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases
AU - Blue Mountains Eye Study—GWAS group
AU - NEIGHBORHOOD Consortium
AU - Wellcome Trust Case Control Consortium 2
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 - Tham, Yih Chung
AU - Haines, Jonathan L.
AU - Kearns, Lisa S.
AU - Hayward, Caroline
AU - Shi, Yuan
AU - Van Leeuwen, Elisabeth M.
AU - Taylor, Kent D.
AU - Wang, Jie Jin
AU - Rochtchina, Elena
AU - Attia, John
AU - Scott, Rodney
AU - Holliday, Elizabeth G.
AU - Baird, Paul N.
AU - Xie, Jing
AU - Inouye, Michael
AU - Viswanathan, Ananth
AU - Sim, Xueling
AU - Bonnemaijer, Pieter
AU - Rotter, Jerome I.
AU - Martin, Nicholas G.
AU - Zeller, Tanja
AU - Mills, Richard A.
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 - Scott, William K.
AU - Donnelly, Peter
AU - Palmer, Colin N.A.
AU - Souzeau, Emmanuelle
PY - 2018/12/1
Y1 - 2018/12/1
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.
KW - ADAMTS Proteins/genetics
KW - Asian Continental Ancestry Group
KW - Cornea/abnormalities
KW - Corneal Diseases/ethnology
KW - Corneal Dystrophies, Hereditary/ethnology
KW - Decorin/genetics
KW - Ehlers-Danlos Syndrome/ethnology
KW - European Continental Ancestry Group
KW - Eye Diseases, Hereditary/ethnology
KW - Fibrillin-1/genetics
KW - Gene Expression
KW - Genome, Human
KW - Genome-Wide Association Study
KW - Glaucoma, Open-Angle/ethnology
KW - Humans
KW - Keratoconus/ethnology
KW - Loeys-Dietz Syndrome/ethnology
KW - Lumican/genetics
KW - Marfan Syndrome/ethnology
KW - Mendelian Randomization Analysis
KW - Myopia/ethnology
KW - Polymorphism, Single Nucleotide
KW - Proteoglycans/genetics
KW - Quantitative Trait Loci
KW - Quantitative Trait, Heritable
KW - Transforming Growth Factor beta2/genetics
UR - http://www.scopus.com/inward/record.url?scp=85047061045&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03646-6
DO - 10.1038/s41467-018-03646-6
M3 - Article
C2 - 29760442
AN - SCOPUS:85047061045
SN - 2041-1723
VL - 9
SP - 1864
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1864
ER -