A Shared Genetic Basis Underlying Myopia-Exotropia Comorbidity

To characterize the shared genetic architecture underlying the frequent co-occurrence of myopia and exotropia.

Leveraging large-scale genome-wide association study (GWAS) data, we examined the genetic correlation and polygenic overlap between myopia and exotropia. Candidate shared signals were prioritized through cross-trait meta-analysis using multi-trait analysis of GWAS (MTAG) and further evaluated by colocalization, fine mapping, and local genetic correlation analyses, complemented by in silico transcriptomic and regulatory annotation.

High-definition likelihood (HDL) analysis estimated a positive genetic correlation between myopia and exotropia (rg = 0.25; P = 0.044). MiXeR bivariate causal-mixture modeling further demonstrated substantial polygenic overlap, estimating 201 shared non-null variants with 80.1% concordant effect directions. This shared component accounted for a larger proportion of the polygenicity of exotropia (59.6%) than of myopia (17.9%). MTAG-based cross-trait meta-analysis prioritized rs7405453 at the TSPAN10 locus, previously associated with broadly defined strabismus and refractive error, as the strongest shared signal. The myopia-exotropia genetic correlation changed minimally after exclusion of the TSPAN10 region, indicating that the shared architecture was not driven solely by this locus. In silico transcriptomic and regulatory annotations provided supportive biological context for TSPAN10 across neural, ocular, and extraocular muscle contexts.

The comorbidity of myopia and exotropia may be partly explained by a shared genetic architecture. Further studies with larger samples, refined phenotyping, and functional validation are warranted to clarify the underlying mechanisms.