Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Abstract

Objective Observational studies have indicated that life course adiposity is associated with amyotrophic lateral sclerosis (ALS). However, whether such an association reflects causality remains unclear. We aimed to determine whether life course adiposity such as birth weight (BW), childhood body mass index (BMI), adult BMI, body fat percentage (BF%), and waist‐to‐hip ratio (WHR) have causal effects on ALS. Methods Single nucleotide polymorphisms (SNPs) significantly associated with life course adiposity were used as instrumental variables to estimate the causal effects on ALS. We used summary‐level data from a cohort of 20,806 cases and 59,804 controls in a Mendelian randomization (MR) framework. Results Genetically predicted one standard deviation (1‐SD) increase in BF% was associated with lower risk of ALS (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.54–0.83, p = 3.25E–04) after Bonferroni correction (p < 0.05/5). Genetically predicted 1‐SD higher childhood BMI was suggestively associated with lower risk of ALS (OR = 0.88, 95% CI = 0.78–0.99, p = 0.031). The weighted median method indicated a suggestive association between BMI and ALS (OR = 0.86, 95% CI = 0.69–0.96, p = 0.016). Neither a genetically predicted 1‐SD increase in BW (inverse variance weighted [IVW]: OR = 1.01, 95% CI = 0.87–1.17, p = 0.939) nor WHR adjusted for BMI (IVW: OR = 0.90, 95% CI = 0.76–1.05, p = 0.178) was associated with ALS. Interpretation Our findings provide novel evidence supporting a causal role of higher adiposity, taken as a whole, on lower risk of ALS. A deeper understanding of the energy metabolism of ALS is more likely to identify feasible nutritional interventions and even novel therapeutic targets that might improve the survival of ALS patients. Ann Neurol 2020;87:434–441

Shared genetic links between amyotrophic lateral sclerosis and obesity-related traits: a genome-wide association study

“…Notably, in the 6 shared risk loci identi ed between ALS and BMI, 5 were in reverse effect direction for ALS and BMI in the original GWAS. This is in line with recent Mendelian randomization results [37] that premorbid higher BMI contributes to decreased ALS risk. In contrast, the effect direction of the two shared risk SNPs between ALS and HDL-C were not consistent.…”

Assessment of Bidirectional Relationships Between 98 Genera of the Human Gut Microbiota and Amyotrophic Lateral Sclerosis: A 2-Sample Mendelian Randomization Study

“…The detailed approach of selection of IVs for exposures, genome-wide association study (GWAS) summary statistics for ALS, and MR analysis were previously described [15]. The MR approach we used was based on the following three assumptions: 1) genetic variants (single nucleotide polymorphisms (SNPs)) used as IVs are associated with exposures; 2) genetic variants are not associated with confounders; and 3) genetic variants in uence the risk of outcomes only through interested exposures , not through other pathways [16] (Figure 1).…”

Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…Ahmad Aziz, MD, PhD 1,2 I read with interest the article by Zhang et al who assessed the association between life-course measures of adiposity and the risk of developing amyotrophic lateral sclerosis (ALS). 1 Although I agree with the authors that previous literature suggests that disturbances of systemic energy metabolism could be involved in the pathogenesis of ALS, 2 there seems to be a critical inconsistency in the paper that might invalidate the main finding (ie, the purported association between body fat percentage and risk of ALS). As described in the Methods section of the paper, the authors used inverse variance weighing (IVW) as their main analysis method.…”

“…Reply to "Life Course Adiposity and Amyotrophic Lateral Sclerosis" Linjing Zhang, MD, 1 Tao Huang, PhD, 2 and Dongsheng Fan, MD, PhD 1 We thank Dr N. Ahmad Aziz for his interest in our article. Dr Aziz pointed out that our result for the relation between body fat percentage (BF%) and amyotrophic lateral sclerosis (ALS) risk with inverse variance weighing (IVW) was difficult to reconcile with some of the paper's findings.…”