A review of Mendelian randomization in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities.

Julian TH ，Boddy S ，Islam M ，Kurz J ，Whittaker KJ ，Moll T ，Harvey C ，Zhang S ，Snyder MP ，McDermott C ，Cooper-Knock J ，Shaw PJ ... -  《-》

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Wang Y ，Shen O ，Xu Q ，Sun L ，Jia Y ，Liu Y ，He Y ，Chang X ，Guo D ，Shi M ，Chen GC ，Zheng J ，Zhu 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》

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 ... -  《-》

Identification of potential drug targets for amyotrophic lateral sclerosis by Mendelian randomization analysis based on brain and plasma proteomics.

Amyotrophic lateral sclerosis as a fatal neurodegenerative disease currently lacks effective therapeutic agents. Thus, finding new therapeutic targets to drive disease treatment is necessary. In this study, we utilized brain and plasma proteins as genetic instruments obtained from genome-wide association studies to conduct a Mendelian randomization analysis to identify potential drug targets for amyotrophic lateral sclerosis. Additionally, we validated our results externally using other datasets. We also used Bayesian co-localization analysis and phenotype scanning. Furthermore, we constructed a protein-protein interaction network to elucidate potential correlations between the identified proteins and existing targets. Mendelian randomization analysis indicated that elevated levels of ANO5 (OR = 1.30; 95 % CI, 1.14-1.49; P = 1.52E-04), SCFD1 (OR = 3.82; 95 % CI, 2.39-6.10; P = 2.19E-08), and SIGLEC9 (OR = 1.05; 95% CI, 1.03-1.07; P = 4.71E-05) are associated with an increased risk of amyotrophic lateral sclerosis, with external validation supporting these findings. Co-localization analysis confirmed that ANO5, SCFD1, and SIGLEC9 (coloc.abf-PPH4 = 0.848, 0.984, and 0.945, respectively) shared the same variant with amyotrophic lateral sclerosis, further substantiating potential role of these proteins as a therapeutic target. There are interactive relationships between the potential proteins and existing targets of amyotrophic lateral sclerosis. Our findings suggested that elevated levels of ANO5, SCFD1, and SIGLEC9 are connected with an increased risk of amyotrophic lateral sclerosis and might be promising therapeutic targets. However, further exploration is necessary to fully understand the underlying mechanisms involved.

Yang N ，Shi L ，Xu P ，Ren F ，Li C ，Qi X ... -  《-》