Abstract
BackgroundAssociations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations. However, whether such associations are causal remains largely unknown.MethodsWe employed a two-sample Mendelian randomization approach to evaluate the causal relationship of T2D with the risk of ALS in both European and East Asian populations. Our analysis was implemented using summary statistics obtained from large-scale genome-wide association studies with ~660,000 individuals for T2D and ~81,000 individuals for ALS in the European population, and ~191,000 individuals for T2D and ~4100 individuals for ALS in the East Asian population. The causal relationship between T2D and ALS in both populations was estimated using the inverse-variance-weighted methods and was further validated through extensive complementary and sensitivity analyses.ResultsUsing multiple instruments that were strongly associated with T2D, a negative association between T2D and ALS was identified in the European population with the odds ratio (OR) estimated to be 0.93 (95% CI 0.88–0.99, p = 0.023), while a positive association between T2D and ALS was observed in the East Asian population with OR = 1.28 (95% CI 0.99–1.62, p = 0.058). These results were robust against instrument selection, various modeling misspecifications, and estimation biases, with the Egger regression and MR-PRESSO ruling out the possibility of horizontal pleiotropic effects of instruments. However, no causal association was found between T2D-related exposures (including glycemic traits) and ALS in the European population.ConclusionOur results provide new evidence supporting the causal neuroprotective role of T2D on ALS in the European population and provide empirically suggestive evidence of increasing risk of T2D on ALS in the East Asian population. Our results have an important implication on ALS pathology, paving ways for developing therapeutic strategies across multiple populations.
Highlights
Associations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations
While we primarily focused on examining the causal association between T2D and ALS, we attempted to perform Mendelian randomization (MR) to estimate the causal effects of multiple T2D-related glycemic/anthropometric traits on ALS in the European population
This inverse association can be observed when another set of 90 T2D instruments obtained from a separate study was used, further supporting our results
Summary
Associations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations. Whether such associations are causal remains largely unknown. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by rapid motor neuron degeneration and subsequent respiratory failure [1]. ALS is relatively rare worldwide: the standardized disease incidence is about 1.89 and 0.83 per 100,000 person-years of follow-up in the European and East Asian populations, respectively [2]. The population-wide national economic burden of ALS is estimated to be ~$1.023 billion in the USA, far greater than that of the other two common neuromuscular diseases (Duchenne muscular dystrophy and myotonic dystrophy) [5]. Identifying causal risk factors for ALS can potentially lead to the discovery of new pathogenic pathways underlying ALS, guide the development of effective medical treatment and patient care, and facilitate healthcare policy making and healthcare resource allocation
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