Abstract
OBJECTIVE: To systematically investigate causal relationships between educational attainment, cognitive-related phenotypes, and amyotrophic lateral sclerosis (ALS). METHODS: Summary statistics from genome-wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two-sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them. RESULTS: Genetically predisposition to longer educational attainment and harder math class taken were associated with significantly lower statistical odds ratio of ALS. For per year increase in education completed there was a 21% lower (95% confidence interval [CI] = 27-14%) in risk for ALS. For per 1-SD increase in the highest math class taken obtained there was a 19% lower (95% CI = 9-28%) in risk for ALS. Genetically predisposition to math ability, cognitive performance, and intelligence did not decrease the risk of ALS. INTERPRETATION: This study provides genetic support for a causal association between higher educational attainment and a lower risk of ALS. The genes related to these phenotypes are involved in almost all aspects of neuron-to-neuron communication. ALS patients are occasionally accompanied by varying degrees of cognitive impairment. People with greater cognitive reserve may be better able to offset damages of degenerative brain changes associated with dementia or other brain diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or ALS.