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Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Published version
Peer-reviewed

Type

Article

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Authors

Iglesias, Adriana I  ORCID logo  https://orcid.org/0000-0001-5532-764X
Mishra, Aniket 
Vitart, Veronique 
Bykhovskaya, Yelena 
Höhn, René 

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.

Description

Keywords

ADAMTS Proteins, Asian People, Cornea, Corneal Diseases, Corneal Dystrophies, Hereditary, Decorin, Ehlers-Danlos Syndrome, Eye Diseases, Hereditary, Fibrillin-1, Gene Expression, Genome, Human, Genome-Wide Association Study, Glaucoma, Open-Angle, Humans, Keratoconus, Loeys-Dietz Syndrome, Lumican, Marfan Syndrome, Mendelian Randomization Analysis, Myopia, Polymorphism, Single Nucleotide, Proteoglycans, Quantitative Trait Loci, Quantitative Trait, Heritable, Transforming Growth Factor beta2, White People

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)