Study Finds Six Previously Unreported Genetic Variants Linked to Strabismus

Of the loci in the three meta-analyses, MAD1L1, UTS2, NPLOC4, CHRNA4 and ZNF701 were associated with lung function or smoking, while NPLOC4-TSPAN10-PDE6G-FAAP100 and COL6A1 were linked with myopia. Photo: Getty Images. Click image to enlarge. Strabismus is a relatively common ophthalmic condition; however, there is still much to learn about why it occurs. With complex genetic and environmental causes at play, risk factors for its manifestation are not fully understood. In new research, Australian investigators outlined findings from a large meta-analysis comprising 11 European ancestry genome-wide association studies (GWAS); included were 20,464 cases, 954,921 controls, with subtypes of esotropia (ET) and exotropia (XT) being analyzed as well.It was found that four loci (NPLOC4-TSPAN10-PDE6G-FAAP100, COL6A1, ZNF701 and CHRNA4) were significantly associated with strabismus and five loci for strabismus subtypes. Within the subtypes and using an ET definition, four significant variants were identified in or near UTS2, CHRNA4, DYNLRB2 and NPLOC4-TSPAN10-PDE6G-FAAP100. Using the XT definition, two significant independent variants included UTS2 and MAD1L1. Categorically, the gene cluster NPLOC4-TSPAN10-PDE6G-FAAP100 was tied to strabismus and both subtypes, while CHRNA4 was linked with broad-sense strabismus and ET and UTS2 was linked with ET and XT. In all, seven strabismus-associated loci were identified across the definitions.The authors of the study note in their paper for Nature Communications that strabismus is a heterogeneous condition, with some genetic factors that may be common across subtypes, but with others that may exist solely to specific forms. Related to this, they believe their results “indicate that the statistical power of meta-analysis varies depending on the definition of strabismus used in the clinical data, suggesting that subtype-specific genetic factors may influence the susceptibility to different forms of strabismus. The low genetic correlation between ET and XT suggests that these sub-phenotypes have different biological mechanisms.”Also supporting this idea is the fact that the locus NPLOC4-TSPAN10-PDE6G-FAAP100 did not reach genome-wide significance with XT, but did with broad-sense strabismus and ET, thus highlighting the potential differing biological mechanisms that result in ET and XT.Additionally, the researchers successfully replicated a previous report finding the strabismus variant near NPLOC4-TSPAN10-PDE6G-FAAP100, as well as finding that, using Mendelian randomization, genetic evidence supported a causal link between maternal smoking and strabismus development.As for the link with maternal smoking, this relationship stems from previous observational studies having reported significant effects on vision health pertaining to their children. The researchers here used the well-established maternal smoking proxy instrumental variable—rs16969968—to show that maternal smoking during pregnancy is indeed associated with broadly defined strabismus, ET and XT.As the authors add to this particular point, “we obtained strong genetic evidence supporting a causal link between maternal smoking and strabismus. Thus, this work augments ongoing public health efforts aimed at reducing the rate of maternal smoking.”Click here for the journal source. He W, van der Most PJ, Ong JS, et al.; Lifelines Cohort Study. Large-scale GWAS of strabismus identifies risk loci and provides support for a link with maternal smoking. Nat Commun. 2025;16:7890. This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.