Risk Of Amyotrophic Lateral Sclerosis Research Articles

Physical activities and risk of neurodegenerative diseases: A two-sample Mendelian randomization study.

ObjectivesPhysical activity (PA) is considered beneficial in slowing the progression and improving the neurodegenerative disease prognosis. However, the association between PA and neurodegenerative diseases remains unknown. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal association between PA phenotypes and neurodegenerative diseases.Materials and methodsGenetic variants robustly associated with PA phenotypes, used as instrumental variables, were extracted from public genome-wide association study (GWAS) summary statistics. Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), were considered outcomes. GWAS information was also obtained from the most recent large population study of individuals with European ancestry. Multiple MR methods, pleiotropy tests and sensitivity analyses were performed to obtain a robust and valid estimation.ResultsWe found a positive association between moderate-to-vigorous physical activities and ALS based on the inverse variance weighted MR analysis method (OR: 2.507, 95% CI: 1.218–5.160, p = 0.013). The pleiotropy test and sensitivity analysis confirmed the robustness and validity of these MR results. No causal effects of PA phenotypes were found on PD and AD.ConclusionOur study indicates a causal effect of PA on the risk of neurodegenerative diseases. Genetically predicted increases in self-reported moderate-to-vigorous PA participation could increase the risk of ALS in individuals of European ancestry. Precise and individualized prescriptions of physical activity should be provided to the elderly population.

Use of gradient boosting machine for exposome-wide analyses: application for pharmaceutical risk factors for amyotrophic lateral sclerosis

Background Accumulating evidence suggests that human health is affected by a complex set of exposures, including to environmental toxicants, dietary constituents, psychosocial stressors, and physical factors. Capturing the complexity of the whole exposome is pivotal for advancing etiological knowledge, yet standard statistical methods, as well as recent developments for mixtures analysis, are limited to considering only a modest number of exposures and interactions while often also making the implicit assumption that the exposures are continuous. Machine learning approaches could offer benefits in these very high-dimensional settings. Method Using gradient boosted decision trees coupled with Bayesian model optimization and a nested cross-validation design, we describe an approach for outcome prediction based on a mixture of exposures, and for identification of specific culprit factors within the mixture that consistently drive the association while allowing for synergistic or antagonistic interactions between the predictors. While this flexible approach is applicable to many settings, we used it to evaluate the association between patients’ history of medication use and risk of amyotrophic lateral sclerosis (ALS), as a steppingstone for integrating additional exposures and in a setting that largely avoids exposure measurement errors that further complicate many toxicant mixtures. Results Of nearly 800 binary predictors, we identified 7 medication classes that were consistently associated with ALS risk across independently trained models. Interactions between medication groups did not substantially affect the risk. Prediction accuracy was consistent, but low due to the lack of information on other etiological risk factors for ALS. Summary The described methodology allows to predict the overall effect of a mixture and to identify specific culprit factors in very high dimensional settings and when both continuous and categorical exposures are of interest. While causal interpretation of purely predictive models should generally be avoided, the repeated sampling of the dataset has interesting causal inference implications.

A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression.

We describe the characterisation of a variable number tandem repeat (VNTR) domain within intron 1 of the amyotrophic lateral sclerosis (ALS) risk gene CFAP410 (Cilia and flagella associated protein 410) (previously known as C21orf2), providing insight into how this domain could support differential gene expression and thus be a modulator of ALS progression or risk. We demonstrated the VNTR was functional in a reporter gene assay in the HEK293 cell line, exhibiting both the properties of an activator domain and a transcriptional start site, and that the differential expression was directed by distinct repeat number in the VNTR. These properties embedded in the VNTR demonstrated the potential for this VNTR to modulate CFAP410 expression. We extrapolated these findings in silico by utilisation of tagging SNPs for the two most common VNTR alleles to establish a correlation with endogenous gene expression. Consistent with in vitro data, CFAP410 isoform expression was found to be variable in the brain. Furthermore, although the number of matched controls was low, there was evidence for one specific isoform being correlated with lower expression in those with ALS. To address if the genotype of the VNTR was associated with ALS risk, we characterised the variation of the CFAP410 VNTR in ALS cases and matched controls by PCR analysis of the VNTR length, defining eight alleles of the VNTR. No significant difference was observed between cases and controls, we noted, however, the cohort was unlikely to contain sufficient power to enable any firm conclusion to be drawn from this analysis. This data demonstrated that the VNTR domain has the potential to modulate CFAP410 expression as a regulatory element that could play a role in its tissue-specific and stimulus-inducible regulation that could impact the mechanism by which CFAP410 is involved in ALS.

Selenoprotein P Concentrations in the Cerebrospinal Fluid and Serum of Individuals Affected by Amyotrophic Lateral Sclerosis, Mild Cognitive Impairment and Alzheimer's Dementia.

Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case–control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status.

Medication use and risk of amyotrophic lateral sclerosis—a systematic review

BackgroundStudying whether medications act as potential risk factors for amyotrophic lateral sclerosis (ALS) can contribute to the understanding of disease etiology as well as the identification of novel therapeutic targets. Therefore, we conducted a systematic review to summarize the existing evidence on the association between medication use and the subsequent ALS risk.MethodsA systematic review was conducted in Medline, Embase, and Web of Science from the date of database establishment to December 10, 2021. References of identified articles were further searched for additional relevant articles. Studies were included if (1) published in English, (2) explored medication use as exposure and development of ALS as outcome, and (3) the design was a human observational study. Clinical trials, reviews, comments, editorials, and case reports were excluded. Quality assessment was performed using a pre-validated tool for non-randomized studies, the Newcastle–Ottawa Assessment Scale (NOS).ResultsOf the 4760 studies identified, 25 articles, including 13 case–control studies, five nested case–control studies, six cohort studies, and one retrospective chart review, were included in the review. Among these studies, there were 22 distinct study populations that included 171,407 patients with ALS, seven classes of medication examined, and 23 studies with a NOS ≥ 5. There was a general lack of agreement between studies on the associations of cholesterol-lowering drugs, anti-inflammatory drugs, immunosuppressants, antibiotics, oral contraceptives (OCs) or hormone replacement therapy (HRT), antihypertensive drugs, antidiabetics, and drugs for psychiatric and neurological disorders with the subsequent risk of ALS. However, it appeared that statins, aspirin, OCs/HRT, antihypertensives, and antidiabetics were unlikely related to a higher risk of ALS. The positive associations noted for antibiotics, antidepressants, and skeletal muscle relaxants might be attributable to prodromal symptoms of ALS.ConclusionsThere is currently no strong evidence to link any medication use with ALS risk.

The repeat length of C9orf72 is associated with the survival of amyotrophic lateral sclerosis patients without C9orf72 pathological expansions

ObjectiveTo explore whether the repeat lengths of the chromosome 9 open reading frame 72 (C9orf72) gene and the ataxin-2 (ATXN2) gene in amyotrophic lateral sclerosis (ALS) patients without C9orf72 repeat expansions confer a risk of ALS or survival disadvantages in ALS.MethodsWe screened a hospital-based cohort of Chinese patients with sporadic ALS without C9orf72 repeat expansions and neurologically healthy controls for C9orf72 GGGGCC and AXTN2 CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum C9orf72 and ATXN2 repeat alleles, such as sex, age of onset, diagnostic delay, and survival.ResultsOverall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the C9orf72 and ATXN2 were both detected. We found significant survival differences in patients using a series of C9orf72 repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank p = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03–1.05, p < 0.001], diagnostic delay (0.95, 0.94–0.96, p < 0.001), and carrying C9orf72 repeat length of 2 (0.72, 0.59–0.89, p = 0.002) in the survival of patients without C9orf72 repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum C9orf72 repeat allele over 2 (1.81, 1.32–2.48, p < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of ATXN2 or stratified by C9orf72 repeats of 2.ConclusionThe length of 2 in the maximum C9orf72 repeat allele was identified to be associated with favorable survival in ALS patients without C9orf72 repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.

Amyotrophic lateral sclerosis and cerebellum

Amyotrophic lateral sclerosis (ALS) is a devastating, heterogeneous neurodegenerative neuromuscular disease that leads to a fatal outcome within 2–5 years, and yet, a precise nature of the association between its major phenotypes and the cerebellar role in ALS pathology remains unknown. Recently, repeat expansions in several genes in which variants appreciably contribute to cerebellar pathology, including C9orf72, NIPA1, ATXN2 and ATXN1, have been found to confer a significant risk for ALS. To better define this relationship, we performed MAGMA gene-based analysis and tissue enrichment analysis using genome-wide association study summary statistics based on a study of 27,205 people with ALS and 110,881 controls. Our preliminary results imply a striking cerebellar tissue specificity and further support increasing calls for re-evaluation of the cerebellar role in the ALS pathology.

Questioning the Association of the STMN2 Dinucleotide Repeat With Amyotrophic Lateral Sclerosis.

ObjectivesRecently, the number of dinucleotide CA repeats in an intron of the STMN2 gene was reported to be associated with an increased risk for amyotrophic lateral sclerosis (ALS). Therefore, we sought to replicate this observation in an independent group of ALS patients and a much larger control group.MethodsHere, we used whole-genome sequencing and tested the STMN2 CA repeat in a case-control cohort of the European genetic background and in genomes from various populations in the gnomAD cohort to attempt to replicate this proposed association.ResultsWe find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Furthermore, we did not observe an association between longer STMN2 CA repeats and ALS phenotype.DiscussionIn summary, our results do not support a role of STMN2 CA repeats toward ALS risk. As TDP-43 aggregation is central to ALS pathogenesis, lowered expression of STMN2 could be used as a biomarker for ALS. Therefore, a variant associated both with the risk for ALS and the level of STMN2 expression would be clinically useful. However, for a variant to be actionable, it must be strongly replicated in independent cohorts and exceed the rigorous statistical thresholds applied.

Incidence of amyotrophic lateral sclerosis in older adults.

We investigated the age- and sex-specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. We identified all incident ALS cases within a population-based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person-years at risk for ALS). We calculated age- and sex-specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. The overall incidence for our most inclusive definition was 22.84 per 100 000 person-years for men and 16.05 per 100 000 person-years for women. The overall incidence was 5.72 per 100 000 person-years for men and 3.99 per 100 000 person-years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis.

A strong association between VEGF-A rs28357093 and amyotrophic lateral sclerosis: a brazilian genetic study.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease that affects motor neurons and promotes progressive muscle atrophy. Vascular Endothelial Growth Factor A (VEGF-A) plays multiple roles in the central nervous systems (CNS). The purpose of this study was to evaluate the association between single nucleotide polymorphism (SNP) VEGF-A rs28357093 and ALS. This case-control study was conducted in 101 ALS patients and 119 healthy individuals. Genotyping was performed by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP). The statistical analysis was carried out using the RStudio® and SNPStats© software's. Analysis of genetic inheritance models was performed by logistic regression. Our findings demonstrated a strong association between VEGF- A rs28357093 and ALS in all genetic inheritance models, with a 9-fold increased risk for A/C - C/C genotypes (95%CI = 3.70-21.88; p < 0.001). The mutant allele was more frequent in ALS patients (p < 0.001) and this finding could be associated with ALS risk. This first study from the Brazilian central population was conducted to provide new insight into the pathogenesis of ALS.

Medications on hypertension, hyperlipidemia, diabetes, and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

To investigate the association between the use of common medications on hypertension, hyperlipidemia, diabetes, and the risk of amyotrophic lateral sclerosis (ALS). PubMed, EMBASE, OVID, and Web of Science were searched systematically until December 2021 for studies quantitatively investigating the effect of medications on hypertension, hyperlipidemia, and diabetes on the risk of ALS. We conducted a fixed-effects model or random-effects meta-analysis to calculate the summary ORs (odds ratios) and 95%CIs (confidence intervals). Regular intake of angiotensin-converting enzyme inhibitors (ACEIs) (OR: 0.81, 95%CI: 0.74, 0.89), beta-blockers (OR: 0.82, 95%CI: 0.76, 0.90), calcium-channel blockers (CCBs) (OR: 0.85, 95%CI: 0.79, 0.93), or diuretics (OR: 0.87, 95%CI: 0.81, 0.93) was inversely associated with the incidence of ALS. There was no significant association between statin use and risk of ALS (OR: 0.92, 95%CI: 0.83, 1.03). Metformin (OR: 0.83, 95%CI: 0.75, 0.93) and sulfonylureas (OR: 0.79, 95%CI:0.71, 0.89) use could significantly reduce the risk of ALS. Regular use of anti-hypertensive drugs and anti-diabetes including ACEIs, beta-blockers, CCBs, diuretics, metformin, and sulfonylureas could protect against the incidence of ALS. No significant association between anti-hyperlipidemia drug use and risk of ALS was revealed. Regular medications for hypertension, hyperlipidemia, and diabetes should be recommended regardless of the diagnosis of ALS.

Association Between C-Reactive Protein and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

Background: Until now, the relationship between C-reactive protein (CRP) levels and amyotrophic lateral sclerosis (ALS) risk has not been fully established. It is necessary to assess whether there is a causal relationship between C-reactive protein levels and ALS risk. Objective and Methods: We aimed to determine whether CRP has causal effects on risk of ALS. In this present study, summary-level data for ALS (20,806 cases and 59,804 controls) was obtained from large analyses of genome-wide association studies. For instrumental variables, 37 single nucleotide polymorphisms that had been previously identified to be related to CRP levels were used, including 4 SNPs of conservative CRP genetic variants and 33 SNPs of liberal CRP genetic variants. MR estimates were calculated using the inverse-variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. Results: There was no significant causal relationship between genetically predicted CRP levels and ALS risk (OR = 1.123, 95% CI = 0.963–1.309, p = 0.139) and results for the conservative CRP instruments were consistent (OR = 0.964, 95% CI = 0.830–1.119, p = 0.628). Pleiotropic bias was not observed in this study. Conclusions: This study suggests that genetically predicted CRP levels may not be a causal risk factor for ALS.

Associations of self-reported occupational exposures and settings to ALS: a case–control study

BackgroundEnvironmental exposures contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal and progressive neurological disease. Identification of these exposures is important for targeted screening and risk factor modification.ObjectiveTo identify occupational exposures that are associated with a higher risk of ALS using both survey and standard occupational classification (SOC) coding procedures, and to highlight how exposure surveys can complement SOC coding.MethodsALS participants and neurologically healthy controls recruited in Michigan completed a detailed exposure assessment on their four most recent and longest held occupations. Exposure scores were generated from the exposure survey, and occupations were assigned to SOC codes by experienced exposure scientists.ResultsThis study included 381 ALS and 272 control participants. ALS participants reported higher duration-adjusted occupational exposure to particulate matter (OR = 1.45, 95% CI 1.19–1.78, p < 0.001), volatile organic compounds (OR = 1.22, 95% CI 1.02–1.45, p = 0.029), metals (OR = 1.48, 95% CI 1.21–1.82, p < 0.001), and combustion and diesel exhaust pollutants (OR = 1.20, 95% CI 1.01–1.43, p = 0.041) prior to ALS diagnosis, when adjusted for sex, age, and military service compared to controls. In multivariable models, only occupational exposure to metals remained significant risk (OR = 1.56, 95% CI 1.11–2.20, p = 0.011), although in an adaptive elastic net model, particulate matter (OR = 1.203), pesticides (OR = 1.015), and metals (1.334) were all selected as risk factors. Work in SOC code “Production Occupations” was associated with a higher ALS risk. SOC codes “Building and Grounds Cleaning and Maintenance Occupations”, “Construction and Extraction Occupations”, “Installation, Maintenance, and Repair Occupations”, and “Production Occupations” were all associated with a higher exposure to metals as determined using survey data.DiscussionOccupational exposure to particulate matter, volatile organic compounds, metals, pesticides, and combustion and diesel exhaust and employment in “Production Occupations” was associated with an increased ALS risk in this cohort.

ATXN2 intermediate expansions in amyotrophic lateral sclerosis.

Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis.

NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex genetic architecture. The lengths of two short tandem repeats (STRs), at the NEK1 and STMN2 loci, were recently associated with ALS risk in cohorts of European descent. The STMN2 STR was proposed to be predictive of clinical features including the age of onset and disease duration in bulbar onset cases. We sought to investigate NEK1 and STMN2 STR lengths in a cohort of Australian sporadic ALS cases (n = 608) and neurologically healthy controls (n = 4689) of European ancestry. ExpansionHunter was used to determine NEK1 and STMN2 STR length genotypes from whole-genome sequencing data followed by PCR validation of predicted lengths. No significant association was identified between sporadic ALS risk and the length of either STR. Further, neither NEK1 nor STMN2 STR lengths were indicative of the age of onset or disease duration. We report that the NEK1 and STMN2 STRs were not associated with ALS risk or clinical features in this Australian sporadic ALS cohort.

Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study.

Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.

Progress in Amyotrophic Lateral Sclerosis Gene Discovery: Reflecting on Classic Approaches and Leveraging Emerging Technologies.

Amyotrophic lateral sclerosis (ALS) is the most prominent motor neuron disease in humans. Its etiology consists of progressive motor neuron degeneration resulting in a rapid decline in motor function starting in the limbs or bulbar muscles and eventually fatally impairing central organs most typically resulting in loss of respiration. Pathogenic variants in 4 main genes, SOD1, TARDBP, FUS, and C9orf72, have been well characterized as causative for more than a decade now. However, these only account for a small fraction of all ALS cases. In this review, we highlight many additional variants that appear to be causative or confer increased risk for ALS, and we reflect on the technologies that have led to these discoveries. Next, we call attention to new challenges and opportunities for ALS and suggest next steps to increase our understanding of ALS genetics. Finally, we conclude with a synopsis of gene therapy paradigms and how increased understanding of ALS genetics can lead us to developing effective treatments. Ultimately, a consolidated update of the field can provide a launching point for researchers and clinicians to improve our search for ALS-related genes, defining pathogenic mechanisms, form diagnostics, and develop therapies.

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

ObjectiveSleep 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. MethodsBidirectional 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. ResultsMR 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). ConclusionsAided 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.

Re-analysis of the Hungarian amyotrophic lateral sclerosis population and evaluation of novel ALS genetic risk variants

Amyotrophic lateral sclerosis (ALS) is a presently incurable neurodegenerative disease. Some genes have a causal relationship to ALS, others act as susceptibility and/or risk factors. We aimed to elucidate the role of 14 ALS-related genes in the Hungarian ALS population of 183 patients. Mutation screening of major ALS genes was performed. SMN1 and SMN2 genes were examined by multiplex ligation-dependent probe-amplification assay; intermediate repeat expansions in the ATXN1 and ATXN2 genes were analyzed by fragment analysis. Additional variants in putative ALS genes were screened from previously acquired next generation sequencing data. We confirmed the repeat expansion of the C9orf72, ATXN1 and ATXN2 genes as ALS risk factors in this Hungarian cohort. Additionally, we identified a pathogenic SOD1 mutation and suggested its founder effect. A likely pathogenic variant in the MFSD8 gene was detected, and variants of interest were uncovered in the ANXA11 and GLT8D1 genes. We provide valuable data as part of the growing body of work on population-specific aspects of the genetic background of ALS.

Body Complexion and Circulating Lipids in the Risk of TDP-43 Related Disorders.

ObjectiveFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two distinct degenerative disorders with overlapping genetics, clinical manifestations, and pathology, including the presence of TDP-43 aggregates in nearly 50% of patients with FTD and 98% of all patients with ALS. Here, we evaluate whether different genetically predicted body lipid metabolic traits are causally associated with the risk of FTD with TDP-43 aggregates, compare it to their causal role in the risk of ALS, and identify genetic variants shared between these two TDP43 related disorders in relation to lipid metabolic traits.MethodsWe conducted two-sample Mendelian randomization analyses (2SMR) to evaluate the causal association of 9 body complexion and 9 circulating lipids traits with the risk of FTD with TDP-43 aggregates and the risk of ALS. The inverse-variance weighted method was the primary analysis, followed by secondary sensitive analyses. We then looked for common genetic variants between FTD and ALS in relation to lipid metabolic traits.ResultsGenetically increased trunk-predicted mass, fat-free mass, and higher circulating triglycerides levels were suggestively associated with a higher risk of FTD with TDP-43 aggregates. Circulating lipids, mainly LDL cholesterol, were causally associated with a higher risk of ALS. We identified two genetic variants, EIF4ENIF1 and HNRNPK, in relation to body complexion and circulating lipids shared between FTD with TDP-43 aggregates and ALS.ConclusionThis work provides evidence that body complexion and circulating lipids traits impact differentially on the risk of FTD and ALS, suggesting new and specific interventional approaches in the control of body lipid metabolism for FTD and ALS, and identified HNRNPK as a potential link between circulating lipids levels and these disorders.