Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Abstract

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Figure 1

Relationship between effect sizes on LTL and ALS/FTD for SNPs served as instrumental variables. Results are shown for seven SNPs of ALS (a) and six SNPs of FTD (b) in the European population. Results are also displayed for eight SNPs of ALS in the Asian population (c). In each panel, horizontal/vertical lines represent the 95% confidence intervals.

Figure 2

Statistical power calculation for the causal effect of LTL on ALS estimated with the method proposed in. In the calculation, the total phenotypic variance explained by instrumental variables was 1.26% and the proportion of ALS cases varied from 0.1 to 0.5, the significance level was 0.05, the sample size was 20,000, 37,684, 80,610 or 100,000, and the OR = 1.10 or 1.20.