Shaaban, S and MacKinnon, S and Andrews, C and Staffieri, SE and Maconachie, GDE and Chan, W-M and Whitman, MC and Morton, SU and Yazar, S and MacGregor, S and Elder, JE and Traboulsi, EI and Gottlob, I and Hewitt, AW and Hunter, DG and Mackey, DA and Engle, EC, Strabismus Genetics Research Consortium, Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect, Investigative Ophthalmology & Visual Science, 59, (10) pp. 4054-4064. ISSN 1552-5783 (2018) [Refereed Article]
© 2018 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/
Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted.
Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1.
Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.
|Item Type:||Refereed Article|
|Keywords:||strabismus, esotropia, parent-of-origin, genome-wide association study, WRB|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Ophthalmology and optometry|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Hewitt, AW (Professor Alex Hewitt)|
|UTAS Author:||Mackey, DA (Professor David Mackey)|
|Web of Science® Times Cited:||7|
|Deposited By:||Menzies Institute for Medical Research|
|Downloads:||45 View Download Statistics|
Repository Staff Only: item control page