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Understanding phenotypic connection between type II diabetes (T2D) mellitus and amyotrophic lateral sclerosis (ALS) can offer valuable sight into shared disease etiology and have important implication in drug repositioning and therapeutic intervention.

This work aims to disentangle the nature of the inverse relationship between T2D mellitus and ALS.

Depending on summary statistics of T2D (n = 898 130) and ALS (n = 80 610), we estimated the genetic correlation between them and prioritized pleiotropic genes through a multiple-tissue expression quantitative trait loci–weighted integrative analysis and the conjunction conditional false discovery rate (ccFDR) method. We implemented mendelian randomization (MR) analyses to evaluate the causal relationship between the 2 diseases. A mediation analysis was performed …