Figure 1

Unbiased screen for metabolites linked to ALS risk. (A) Schematic of the study design: We performed an unbiased screen of 566 metabolites using Mendelian randomization (MR) to infer a causal relationship with ALS. Metabolites that passed stringent multiple testing correction were further evaluated using robust MR measures, sensitivity analyses and a validation GWAS. Next, for metabolites that passed all measures, we evaluated other members of their metabolic pathway using orthogonal techniques which utilize common and rare genetic variants so as to infer the underlying biological mechanism. Finally, we evaluated proposed mechanisms of neurotoxicity/neuroprotection in an ALS-relevant disease model. MVMR refers to multivariable Mendelian randomization in which multiple exposures are considered simultaneously. (B) QQ-plot demonstrates that there was no evidence of P-value inflation in our unbiased screen (λ = 1.11); three metabolites were significant after Bonferroni’s multiple testing correction (red line). Blue text denotes a protective association, whereas red text denotes a harmful association.