Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. Methods: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model.
ObjectiveTo determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS).MethodsWe enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient’s disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up.ResultsThe data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (p<0.001). WL occurred in 35.1% of the patients without any symptom of dysphagia. WL is a strong independent predictor of survival, with a dose response relationship between the amount of WL and the risk of death: the risk of death during follow-up increased by 23% for every 10% increase in WL relative to body weight (HR 1.23, 95% CI 1.13 to 1.51, p<0.001).ConclusionsThis population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures.
Under the influence of genes and a varying environment, human brain structure changes throughout the lifespan. Even in adulthood, when the brain seems relatively stable, individuals differ in the profile and rate of brain changes 1 . Longitudinal studies are crucial to identify genetic and environmental factors that influence the rate of these brain changes throughout development 2 and aging 3 . Inter-individual differences in brain development are associated with general cognitive function 4,5 and risk for psychiatric disorders 6,7 and neurological diseases 8,9 . Genetic factors involved in brain development and aging overlap with those for cognition 10 and risk for neuropsychiatric disorders 11 . A recent cross-sectional study showed brain age to be advanced in several brain disorders. Brain age is an estimate of biological age based on brain structure, which can deviate from chronological age. Several shared loci were found between the genome-wide association study (GWAS) summary statistics for advanced brain age and psychiatric disorders 12 . However, information is still lacking on which genetic variants influence an individual's brain changes throughout life, because this requires longitudinal data. Discovering genetic factors that explain variation between individuals in brain structural changes may reveal key biological pathways that drive normal development and aging and may contribute to identifying disease risk and resilience-a crucial goal given the urgent need for new treatments for aberrant brain development and aging worldwide.As part of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium 13 , the ENIGMA Plasticity Working Group quantified the overall genetic contribution to longitudinal brain changes by combining evidence from multiple twin cohorts across the world 14 . Most global and subcortical brain measures showed genetic influences on change over time, with a higher genetic contribution in the elderly (heritability, 16-42%). Genetic factors that influence longitudinal changes were partially independent of those that influence baseline volumes of brain structures, suggesting that there might be genetic variants that specifically affect the rate of development or aging. However, the genes involved in these processes are still not known, with only a single, small-scale GWAS performed for longitudinal volume change in gray and white matter of the cerebrum, basal ganglia and cerebellum 15 . In this study, we set out to find genetic variants that may influence rates of brain changes over time, using genome-wide analysis in individuals scanned with magnetic resonance imaging (MRI) on more than one occasion. We also aimed to identify references
We provide new class I evidence for a positive association between PA and risk of ALS in a large multicentre study using harmonised methodology to objectively quantify PA levels, with some suggestions for population differences.
Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11,700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 x 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
Development of effective treatment for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology and methodological design challenges. Here we have evaluated two major themes in the design of pivotal, phase 3 clinical trials for ALS: (1) patient selection and (2) analytical strategy, and discussed potential solutions with the European Medicines Agency (EMA). Several design considerations were assessed using data from five placebo-controlled clinical trials (N = 988), four population-based cohorts (N = 5,100), and 2,436 placebo-allocated patients from the PRO-ACT database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria and minimizing the exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve a blueprint for future clinical trials in this population.
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