Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.