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. 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

Sherin Shaaban  1   2   3   4 , Sarah MacKinnon  5 , Caroline Andrews  1   6 , Sandra E Staffieri  7   8 , Gail D E Maconachie  9 , Wai-Man Chan  1   6 , Mary C Whitman  2   5   10 , Sarah U Morton  11 , Seyhan Yazar  12   13 , Stuart MacGregor  14 , James E Elder  8   15 , Elias I Traboulsi  16 , Irene Gottlob  9 , Alex W Hewitt  7   13   17 ; Strabismus Genetics Research Consortium; David G Hunter  5   10 , David A Mackey  7   13   17 , Elizabeth C Engle  1   2   3   5   6   18
Affiliations

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

Sherin Shaaban et al. Invest Ophthalmol Vis Sci. .

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.

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Figures

Figure 1
Figure 1
Association results of the nonaccommodative esotropia discovery cohort. (A) Manhattan plot of association results from the discovery data for the nonaccommodative esotropia cohort. The y-axis represents the −log10 (P values). The bolded upper horizontal line indicates the threshold for genome-wide significance (P < 5 × 10−8) and the lower line indicates the threshold for suggestive association (P < 1 × 10−5). The SNP rs2244352 had a P = 2.84 × 10−9. (B) Regional association plot from the discovery nonaccommodative esotropia cohort. The top-ranked SNP, rs2244352, is shown as a solid purple diamond. The color scheme indicates linkage disequilibrium between rs2244352 and other SNPs in the region using the r2 value calculated from the 1000 Genomes project. The y-axis is the −log10 (P value) computed for the displayed SNPs.
Figure 2
Figure 2
DNA-footprinting prediction of the effect of the risk allele [T] on regulatory motifs and two-dimensional heatmap of chromatin interaction in the neighborhood of SNP rs2244352. (A) DNA footprinting predicts that the [T] allele alters the sequence of c-Ets-1 and PU-1 regulatory motifs. Sequence logos were created by CENTIPEDE., (B) UCSC genome browser shot of chromosome 21 (NCBI Build 37; provided in the public domain by University of California-Santa Cruz, https://genome.ucsc.edu/) created by 3D Genome Browser (provided in the public domain by Pennsylvania State University, http://promoter.bx.psu.edu/hi-c) showing WRB and surrounding genes (PSMG1, BRWD1, HMGN1, LCA5L, and SH3BGR) included within a topologically associating domain (TAD) as defined by chromatin conformation capture data (Hi-C profiles). The two-dimensional heatmap represents normalized Hi-C interaction frequencies.
Figure 3
Figure 3
Box plots of WRB, LCA5L, and PSMG1 gene expression for the cis-eQTL rs2244352 in brain cortex. Gene expression levels are stratified by genotype at the SNP rs2244352 cis-eQTL in brain cortex, based on GTEx analysis release V7 (provided in the public domain by The Broad Institute of MIT and Harvard, http://gtexportal.org/). The reference and minor allele [T] is associated with increased risk for nonaccommodative esotropia (P = 2.84 × 10−09), increased expression of WRB and LCA5L (P = 0.0015, 7.5 × 10−10, respectively), and decreased expression of PSMG1 (P = 0.0099). Homo Ref = [TT]; “Het” = [TG]; “Homo Alt” = [GG]. eQTL, expression of a quantitative trait locus; SNP, single nucleotide polymorphism.
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