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 genomewide 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. Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal multisystem neurodegenerative disease, leading to substantial public health threat although it is relatively rare worldwide. However, the cause and pathogenesis underlying ALS mostly remains unknown, with few replicable and definitive risk factors and scarce drugs available 1-4. The number of ALS cases is predicted to increase dramatically due to population aging in the coming years 5 , which would further aggravate the ALS-associated social and economic burden. Therefore, the identification of its risk factors can provide better understanding of ALS and has the potential to pave the way for therapeutic intervention. In the past few years the role of telomere in various complex diseases has attracted much attention 6. Progressive telomere shortening occurs in all dividing normal cells due to incomplete synthesis of DNA lagging-strand, oxidative damage and other factors, which ultimately leads to cellular growth arrest or apoptosis that is thought to be an initial proliferative barrier to tumor development in humans 7. Indeed, recent studies suggested that leukocyte telomere length (LTL) was widely relevant to age-related diseases and disorders (e.g. many types of cancer and coronary heart disease) 8-11. In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer's disease (AD) (Table 1). However, the knowledge about the relationship between LTL and ALS is very limited. Previous studies proposed th...

Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy

“…We did not find further significant associations between genetically predicted TL and other neurodegenerative disease, which also confirms results from previous studies. For instance, two previous MR studies did not find significant causal associations between TL and the risk of PD [21] , ALS and FTD [22] . Additionally, most observational studies showed contradictory results [43] , [44] , [45] .…”

“…Previous MR studies have described potential causal effects of genetically predicted TL on the risk of AD [17] , [18] , [19] , [20] . However, other MR studies failed to provide evidence of causal associations between TL and the risk of Parkinson’s disease (PD) [21] or Amyotrophic lateral sclerosis (ALS) [22] .…”

Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

“…Second, the proportion of phenotypic variance explained by IV-1 was higher than that explained by IV-2; thus, the statistical power of analysis with IV-1 was 40% higher than that of analysis with IV-2 (Table 1 ). Recently, the study published by Gao et al reported that LTL had no direct causal effect on ALS and suggested that shorter LTL can indirectly reduce ALS risk [ 30 ]. Their study was based on IV-2 and an ALS GWAS involving 37,684 individuals of European ancestry [ 31 ].…”

Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

“…Thus, the consequence calculated from IV-1 was treated as the main one in our research and con rmed the studies indicating a protective effect of LTL on ALS. Notably, a similar article recently published showed that LTL had no direct causal effect on ALS and suggested that shorter LTL can reduce the risk of ALS indirectly based on IVs from a GWAS on 37,684 individuals of European ancestry [28,29]. The GWAS was a proxy for exposure measured LTL by quantitative PCR and the power of statistics was declared to be less than 30%.…”