Physical activity and amyotrophic lateral sclerosis: a Mendelian randomization study.

Physical activity (PA) participation has been noted as a potential risk factor for amyotrophic lateral sclerosis (ALS) for decades. However, current studies have been unable to pinpoint the exact relationship between them. Here, we used 2-sample Mendelian randomization (MR), a novel method to systematically investigate causal relationships between PA and ALS. Summary-level data for accelerometer-based and self-reported PA phenotypes were obtained from 2 large genome-wide association studies (GWASs; n = 91,105-377,234), and the ALS summary statistics were from a GWAS of 20,806 cases and 59,804 healthy participants. The present MR study affords no support for causality between 5 included activity habits and ALS. We conclude that PA in the general population is unlikely to affect ALS incidence.

Zhang G ，Zhang L ，Tang L ，Xia K ，Huang T ，Fan D ... -  《-》

Dietary-Derived Essential Nutrients and Amyotrophic Lateral Sclerosis: A Two-Sample Mendelian Randomization Study.

Xia K ，Wang Y ，Zhang L ，Tang L ，Zhang G ，Huang T ，Huang N ，Fan D ... -  《-》

Bidirectional Mendelian randomization to explore the causal relationships between Sleep traits, Parkinson's disease and Amyotrophic lateral sclerosis.

Sleep disturbances have been linked with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) in observational studies, and the comorbidity of PD and ALS has been reported in clinical case reports, but the causalities remain unclear. This study aims to examine bidirectional causal relationships between sleep traits, PD and ALS. Bidirectional two sample Mendelian randomisation (MR) analyses were conducted, with data from individuals of mainly European ancestry. Genetic instruments were obtained from the largest published genome-wide association studies (GWAS) concerning various sleep traits, PD and ALS. MR estimates from each genetic instrument were combined by inverse variance weighted method, with alternate methods (eg, weighted median, MR Egger, MR-PRESSO) and statistical graphs to assess horizontal pleiotropy and remove outliers. MR analysis failed to observe any causal association between sleep disorders and PD, but found a possible causal effect of PD risk on ALS risk (odds ratio [OR] = 1.07; 95% CI: 1.01-1.14, P < 0.01), albeit with a horizontal pleiotropy. Furthermore, MR analyses indicated that excessive daytime sleepiness (EDS) (OR = 2.29; 95% CI: 1.04-5.03, P = 0.04) contributed to a modest increase in risk of ALS, but the reverse causalities were not significant. Higher risk of ALS may be associated with being a "morning person" (OR = 1.03, P = 0.02), a longer sleep duration (OR = 1.01, P < 0.01), and a mean of 9 h or more total sleep duration (β = 0.02, P = 0.04). Aided by large-scale GWAS, a shortage of evidence supporting causal relationships of sleep traits and PD risk, while significant evidence supports that EDS, higher PD risk may causally influence ALS risk. Future researches are required to explore the underlying pathological mechanism as well as the clinically significance, and replicate our findings using independent samples when data become available.

Di H ，Zhu Y ，Xia W ，Meng X ，Zhang M ，Xu M ，Feng J ，Tian Q ，He Y ，Cao S ，Lu Z ... -  《-》

Causal association of type 2 diabetes with amyotrophic lateral sclerosis: new evidence from Mendelian randomization using GWAS summary statistics.

Zeng P ，Wang T ，Zheng J ，Zhou X ... -  《BMC Medicine》

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

Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, whether this association is causal remains unclear. In this study, we aimed to explore the causal relationship between leukocyte telomere length (LTL) and ALS by a two-sample Mendelian randomization (MR) approach. Single-nucleotide polymorphisms (SNPs) for LTL were identified through high-quality genome-wide association studies (GWASs). The ALS GWAS summary data (20,806 cases; 59,804 controls) with largest sample size to date was obtained. We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR-PRESSO method to perform sensitivity analyses. We found that genetically determined increased LTL was inversely associated with the risk of ALS (odds ratio (OR) = 0.846, 95% confidence interval (CI): 0.744-0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. The results were further confirmed by sensitivity analysis with the MR Egger method (OR = 0.647, 95% CI = 0.447-0.936, P = 0.050). Analyses by the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935, P = 0.535) also showed a similar trend. The MR Egger analysis did not suggest directional pleiotropy, with an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Our results suggest that genetically predicted increased LTL has a causal relationship with a lower risk of ALS. Protecting against telomere loss may be of great importance in the prevention and treatment of ALS.

Xia K ，Zhang L ，Zhang G ，Wang Y ，Huang T ，Fan D ... -  《Orphanet Journal of Rare Diseases》