Association of Genetic Variation with Keratoconus

Bennet J. McComish, Srujana Sahebjada, Yelena Bykhovskaya, Colin E. Willoughby, Andrea J. Richardson, Abi Tenen, Jac C. Charlesworth, Stuart MacGregor, Paul Mitchell, Sionne E.M. Lucas, Richard A. Mills, David A. MacKey, Xiaohui Li, Jie Jin Wang, Richard A. Jensen, Jerome I. Rotter, Kent D. Taylor, Alex W. Hewitt, Yaron S. Rabinowitz, Paul N. BairdJamie E. Craig, Kathryn P. Burdon

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    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 6252612 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.

    Original languageEnglish
    Pages (from-to)174-181
    Number of pages8
    JournalJAMA Ophthalmology
    Issue number2
    Early online date19 Dec 2019
    Publication statusPublished (in print/issue) - 1 Feb 2020

    Bibliographical note

    Funding Information:
    Expression Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. The data used for the analyses described in the manuscript were obtained from the Genotype–Tissue Expression Portal on May 27, 2019. This study was supported by the Australian National Health and Medical Research Council (project grant GNT1104700) and Senior Research Fellowships (grant 1138585 [Dr Baird] and 1059954 [Dr Burdon]). The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian Government. The discovery case cohort was funded by a National Health and Medical Research Council Centre for Research Excellence grant (1023911). Control genotype data for the discovery cohort were provided by the International AMD Genetics Consortium genotyped under the Center for Inherited Diseases Research Program (contract number HHSN268201200008I). The US replication cohort is supported in part by the National Eye Institute (grant R01 EY009052). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences (Clinical Translational Science Institute grant UL1TR001881) and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (grant DK063491) to the Southern California Diabetes Endocrinology Research Center. The Cardiovascular Health Study (control cohort) was supported by the National Heart, Lung, and Blood Institute (grants HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, and U01HL130114), with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by the National Institute on Aging (grant R01AG023629).

    Publisher Copyright:
    © 2019 American Medical Association. All rights reserved.

    Copyright 2020 Elsevier B.V., All rights reserved.


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