Genome-wide association study identifies a susceptibility locus for comitant esotropia and suggests a parent-of-origin effect

Sherin Shaaban, Sarah Mackinnon, Caroline Andrews, Sandra E. Staffieri, Gail D. E. Maconachie, Wai-Man Chan, Mary C. Whitman, Sarah U. Morton, Seyhan Yazar, Stuart Macgregor, James E. Elder, Elias I. Traboulsi, Irene Gottlob, Alex W. Hewitt, Strabismus Genetics Research Consortium, David G. Hunter, David A. Mackey, Elizabeth C. Engle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait.

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.
Original languageEnglish
Pages (from-to)4054-4064
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Issue number10
Publication statusPublished - 1 Aug 2018

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • strabismus
  • esotropia
  • parent-of-origin
  • genome-wide association study
  • WRB


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