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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.

Original publication

DOI

10.1038/s41467-018-03646-6

Type

Journal article

Journal

Nat Commun

Publication Date

14/05/2018

Volume

9

Keywords

ADAMTS Proteins, Asian Continental Ancestry Group, Cornea, Corneal Diseases, Corneal Dystrophies, Hereditary, Decorin, Ehlers-Danlos Syndrome, European Continental Ancestry Group, 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