Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.
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.
Duke Scholars
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Related Subject Headings
- White People
- Transforming Growth Factor beta2
- Quantitative Trait, Heritable
- Quantitative Trait Loci
- Proteoglycans
- Polymorphism, Single Nucleotide
- Myopia
- Mendelian Randomization Analysis
- Marfan Syndrome
- Lumican
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- White People
- Transforming Growth Factor beta2
- Quantitative Trait, Heritable
- Quantitative Trait Loci
- Proteoglycans
- Polymorphism, Single Nucleotide
- Myopia
- Mendelian Randomization Analysis
- Marfan Syndrome
- Lumican