Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

Di He,Liying Cui

doi:10.3389/fgene.2021.724903

Abstract

Objectives: The relation between selenium overexposure and increased risk of amyotrophic lateral sclerosis (ALS) has been subject to considerable interest. Epidemiologic studies have reported suggestive associations between selenium and ALS, although the causal inference between selenium and ALS remains to be established. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to analyze the causal role of selenium on ALS risk. Variants associated with selenium levels were obtained from the GWAS meta-analysis of circulating selenium levels (n = 5,477) and toenail selenium levels (n = 4,162) in the European population. Outcome data were from the largest ALS GWAS dataset with 20,806 ALS cases and 59,804 controls in the European population. Inverse variance weighted (IVW) method was used as the main analysis, with an array of sensitivity analyses performed to detect potential violations of MR assumptions. Results: Inverse variance weighted (IVW) analysis indicated no evidence of a causal role for selenium levels in ALS development (odds ratio (OR) = 1.02, 95% confidence interval (CI) = 0.96–1.08). Similar results were observed for the sensitivity analyses (OR = 1.00, 95% CI = 0.95–1.07 for weighted median; OR = 1.07, 95% CI = 0.87–1.32 for MR-Egger), with no pleiotropy detected. Conclusions: Although selenium was found associated with ALS according to earlier epidemiologic studies, current evidence based on the population of European ancestry does not support the causal effect of selenium on ALS risk.

Highlights

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder progressively affecting both upper and lower motor neurons (Swinnen and Robberecht, 2014; Brown and Al-Chalabi, 2017)
12 independent SNPs, all of which were available in the exposure and outcome datasets, were selected as instrumental variables (IVs) (Table 2)
The genetic instruments explained 0.32–1.76% of the variation in circulating and toenail selenium levels, and the F statistics were larger than 10 for all included IVs, which indicate that the instruments used in the MR analysis were unlikely to suffer from weak instrument bias

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder progressively affecting both upper and lower motor neurons (Swinnen and Robberecht, 2014; Brown and Al-Chalabi, 2017) It is considered a complex genetic disease, with Mendelian inheritance pattern observed only in a small number of familial cases (Hardiman et al, 2017; Chia et al, 2018). It has been suggested that the manifestation of ALS is a stepwise process, in which the predisposing variants carried by individuals interact with multiple environmental triggers (Al-Chalabi et al, 2014; Cook and Petrucelli, 2019) Such multistep model empathizes the relevance of studying both genetic and environmental risk factors in ALS (Paez-Colasante et al, 2015). Given the rarity of the disease and ethical issues, it is difficult to conduct unbiased association studies of ALS and selenium in practice

Objectives

Methods

Results

Conclusion