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Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):4054-4064. doi: 10.1167/iovs.18-24082.

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.

Author information

1
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.
2
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.
3
Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States.
4
Dubai Harvard Foundation for Medical Research, Boston, Massachusetts, United States.
5
Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.
6
Howard Hughes Medical Institute, Chevy Chase, Maryland, United States.
7
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
8
Department of Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
9
Department of Neuroscience, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom.
10
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
11
Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, United States.
12
Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
13
Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia.
14
Stastical Genetics Laboratory, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
15
Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia.
16
Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States.
17
Department of Ophthalmology, School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
18
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, United States.

Abstract

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.

PMID:
30098192
PMCID:
PMC6088800
DOI:
10.1167/iovs.18-24082
[Indexed for MEDLINE]
Free PMC Article

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