The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method. We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10-5 as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy. The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results. The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.

Cui Y ，Chen J ，Li H ，Zheng D ，Shi X ... -  《Brain and Behavior》

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 ... -  《-》

Associations of the circulating levels of cytokines with risk of amyotrophic lateral sclerosis: a Mendelian randomization study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is accompanied by muscle weakness and muscle atrophy, typically resulting in death within 3-5 years from the disease occurrence. Though the cause of ALS remains unclear, increasing evidence has suggested that inflammation is involved in the pathogenesis of ALS. Thus, we performed two-sample Mendelian randomization (MR) analyses to estimate the associations of circulating levels of cytokines and growth factors with the risk of ALS. Genetic instrumental variables for circulating cytokines and growth factors were identified from a genome-wide association study (GWAS) of 8293 European participants. Summary statistics of ALS were obtained from a GWAS including 20,806 ALS cases and 59,804 controls of European ancestry. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the simple-median method, weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, a reverse MR analysis was performed to assess the possibility of reverse causation between ALS and the cytokines that we identified. After Bonferroni correction, genetically predicted circulating level of basic fibroblast growth factor (FGF-basic) was suggestively associated with a lower risk of ALS [odds ratio (OR): 0.74, 95% confidence interval (95% CI): 0.60-0.92, P = 0.007]. We also observed suggestive evidence that interferon gamma-induced protein 10 (IP-10) was associated with a 10% higher risk of ALS (OR: 1.10, 95% CI: 1.03-1.17, P = 0.005) in the primary study. The results of sensitivity analyses were consistent. Our systematic MR analyses provided suggestive evidence to support causal associations of circulating FGF-basic and IP-10 with the risk of ALS. More studies are warranted to explore how these cytokines may affect the development of ALS.

Liu B ，Lyu L ，Zhou W ，Song J ，Ye D ，Mao Y ，Chen GB ，Sun 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》

Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis.

Zeng Y ，Guo R ，Cao S ，Chavarria Gonzalez S ，Pang K ，Liu C ，Yang H ... -  《-》