McComish, BJ and Sahebjada, S and Bykhovskaya, Y and Willoughby, CE and Richardson, AJ and Tenen, A and Charlesworth, JC and MacGregor, S and Mitchell, P and Lucas, SEM and Mills, RA and Mackey, DA and Li, X and Wang, JJ and Jensen, RA and Rotter, JI and Taylor, KD and Hewitt, AW and Rabinowitz, YS and Baird, PN and Craig, JE and Burdon, KP, Association of genetic variation with keratoconus, JAMA Ophthalmology pp. 1-8. ISSN 2168-6165 (2019) [Refereed Article]
Copyright 2019 American Medical Association
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.
|Item Type:||Refereed Article|
|Keywords:||keratoconus, genome-wide association study|
|Research Division:||Medical and Health Sciences|
|Research Group:||Clinical Sciences|
|Research Field:||Medical Genetics (excl. Cancer Genetics)|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Hearing, Vision, Speech and Their Disorders|
|UTAS Author:||McComish, BJ (Dr Bennet McComish)|
|UTAS Author:||Charlesworth, JC (Dr Jac Charlesworth)|
|UTAS Author:||Lucas, SEM (Ms Sionne Lucas)|
|UTAS Author:||Hewitt, AW (Professor Alex Hewitt)|
|UTAS Author:||Craig, JE (Mr Jamie Craig)|
|UTAS Author:||Burdon, KP (Professor Kathryn Burdon)|
|Deposited By:||Menzies Institute for Medical Research|
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