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

Nat Commun. 2018 May 14;9(1):1864. doi: 10.1038/s41467-018-03646-6.

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.

Publication types

  • Meta-Analysis

MeSH terms

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

Substances

  • DCN protein, human
  • Decorin
  • FBN1 protein, human
  • Fibrillin-1
  • KERA protein, human
  • LUM protein, human
  • Lumican
  • Proteoglycans
  • TGFB2 protein, human
  • Transforming Growth Factor beta2
  • ADAMTS Proteins
  • ADAMTS2 protein, human

Supplementary concepts

  • Cornea Plana 1