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

Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Emmanuelle Souzeau

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)
220 Downloads (Pure)


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 languageEnglish
Article number1864
Pages (from-to)1864
Number of pages11
JournalNature Communications
Issue number1
Early online date14 May 2018
Publication statusPublished - 1 Dec 2018


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


Dive into the research topics of 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases'. Together they form a unique fingerprint.

Cite this