The causal effect of obesity on concomitant exotropia: A lifecourse Mendelian randomization study

Obesity is now a significant global public health issue. Limited understanding exists regarding the association between obesity and concomitant exotropia. Our objective was to identify the causal relationship between lifecourse obesity, including birth weight, childhood body mass index (BMI), and adult BMI, and the risk of concomitant exotropia. We used a two-sample Mendelian randomization (MR) strategy to examine the causal relationship with inverse-variance weighted method as the primary MR analysis. We carried out sensitivity analyses to evaluate the accuracy and robustness of our findings. Also, we performed reverse-direction MR analysis to eliminate the possibility of reverse causality. Childhood BMI, as opposed to birth weight or adult BMI, had a significant impact on the risk of concomitant exotropia (odds ratio = 1.40, 95% confidence interval (CI): 1.08-1.81, P = .01). This significance persisted even after accounting for birth weight and adult BMI using multivariable MR analysis (odds ratio = 1.35, 95% CI: 1.04-1.75, P = .02). There was no significant heterogeneity or pleiotropy observed in sensitivity analyses (P > .05). Multivariable MR analysis further confirmed the absence of pleiotropic effects of some risk factors including prematurity, maternal smoking around birth and refractive error. Reverse causality did not affect the causal relationship (beta = -0.0244, 95% CI: -0.0545 to 0.0056, P = .11). Genetic predisposition to higher childhood BMI was found to be causally linked to an increased risk of concomitant exotropia.