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Original Investigation
December 19, 2019

Association of Genetic Variation With Keratoconus

Author Affiliations
  • 1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  • 2Centre for Eye Research Australia, Melbourne, Victoria, Australia
  • 3Department of Surgery (Ophthalmology), Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia
  • 4Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
  • 5Cornea Genetic Eye Institute, Beverly Hills, California
  • 6Board of the Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California
  • 7Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom
  • 8Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom
  • 9Vision Eye Institute, Melbourne, Victoria, Australia
  • 10School of Primary and Allied Health Care, Monash University, Melbourne, Victoria, Australia
  • 11Melbourne Stem Cell Centre, Melbourne, Victoria, Australia
  • 12QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 13Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
  • 14Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia
  • 15Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia
  • 16Institute for Translational Genomics and Population Science, Los Angeles Biomedical Research Institute, Los Angeles, California
  • 17Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California
  • 18Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
JAMA Ophthalmol. 2020;138(2):174-181. doi:10.1001/jamaophthalmol.2019.5293
Key Points

Question  Which genetic loci are associated with keratoconus?

Findings  In this case-control genome-wide association study of a discovery cohort and 3 independent replication cohorts, a locus containing multiple variants across 6 protein-coding genes on chromosome 11 was associated with keratoconus. Several of these genes are likely involved in apoptotic pathways.

Meaning  This study of patients with keratoconus and control participants showed a potential role of genes involved in apoptotic pathways.


Importance  Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.

Objective  To identify genetic susceptibility regions for keratoconus in the human genome.

Design, Setting, and Participants  This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10−6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.

Main Outcomes and Measures  Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.

Results  The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10−8), with a P value of 7.46 × 10−9 at rs61876744 in patatin-like phospholipase domain–containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10−12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10−6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10−7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10−8).

Conclusions and Relevance  In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

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