Association Between Premorbid Body Mass Index and Amyotrophic Lateral Sclerosis: Causal Inference Through Genetic Approaches

Purpose: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) was implied in observational studies; however, whether this association is causal remains largely unknown. Materials and Methods: We first conducted a meta-analysis to investigate whether there exits an association between premorbid BMI and ALS. We then employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The Mendelian randomization analysis was implemented using summary statistics for independent instruments obtained from large-scale genome-wide association studies of BMI (up to similar to 770,000 individuals) and ALS (up to similar to 81,000 individuals). The causal effect of BMI on ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses. Results: The meta-analysis showed that a unit increase of premorbid BMI can result in about 3.0% (95% CI 2.1-4.5%) risk reduction of ALS. Using 1,031 instruments that were strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97-1.11, p = 0.275) in the European population. This null association between BMI and ALS also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments. Conclusion: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.