Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

Zhang, Sai; Cooper‐Knock, Johnathan; Weimer, Annika K.; Shi, Minyi; Moll, Tobias; Harvey, Calum; Nezhad, Helia Ghahremani; Franklin, John; Souza, Cleide dos Santos; Wang, Cheng; Li, Jingjing; Eitan, Chen; Hornstein, Eran; Kenna, Kevin P.; Veldink, Jan H.; Ferraiuolo, Laura; Shaw, Pamela J.; Snyder, M

doi:10.2139/ssrn.3744427

Cited by 5 publications

(8 citation statements)

References 88 publications

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“…Vesicle mediated transport is involved in synaptic neurotransmission but also in vesicle fusion, which is an essential component of autophagy ( 57 ). Our study of the genetic architecture of ALS in the context of motor neuron function highlighted function within the distal axon ( 17 ) and demonstrated that axonal dysfunction associated with LoF of KANK1 , a putative new ALS gene, may be upstream of TDP-43 mislocalization.…”

Section: Als Risk Genes Converge In Pathwaysmentioning

confidence: 85%

“…Both regulatory and coding variants within the NEK1 and TBK1 loci are thought to cause loss of function (LoF) of the target gene in ALS patients. Similarly we have profiled ALS-associated regulatory variation and identified other non-GWAS hits where there is a convergence of common and rare variant signal in a LoF mechanism ( 5 , 17 ). Moreover, a similar phenomenon has been reported in other disease areas ( 30 ).…”

Section: Impact Of New Gwasmentioning

confidence: 99%

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Advances in the genetic classification of amyotrophic lateral sclerosis

Cooper‐Knock

Harvey

Zhang

et al. 2021

Current Opinion in Neurology

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Purpose of review Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease where disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture which will be necessary for comprehensive disease subclassification. Recent findings We summarise recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach including clinicians, geneticists and pathologists. Summary The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.

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Section: Als Risk Genes Converge In Pathwaysmentioning

confidence: 85%

Section: Impact Of New Gwasmentioning

confidence: 99%

Advances in the genetic classification of amyotrophic lateral sclerosis

Cooper‐Knock

Harvey

Zhang

et al. 2021

Current Opinion in Neurology

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“…Whole genome sequencing and clinical data of ALS cases from Project MinE (data freeze 2) were used for the survival and age of onset analyses (29,30). Samples were filtered to remove common variants (MAF > 0.01) in the enhancer regions of CAV1 and CAV2 genes, which are defined in Cooper-Knock et al, 2020 (17).…”

Section: Methodsmentioning

confidence: 99%

Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival

Adey

Cooper-Knock

Khleifat

et al. 2022

Preprint

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Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in ALS. Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

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“…Project MinE is at the forefront of these approaches, with efforts to sequence the genome and connect findings with transcriptome, epigenome, and noncoding genome findings. 55,56 Other data sets are also taking integrative approaches and providing resources for researchers at large for straightforward access to sample data. The Answer ALS consortium is one such approach, which provides whole genome data along with induced pluripotent stem cell lines and their corresponding transcriptome data, thereby saving researchers precious time and resources in trying to generate their own version of these lines.…”

Section: Challenges In Als Genetics and Exploring Emerging Solutionsmentioning

confidence: 99%

Progress in Amyotrophic Lateral Sclerosis Gene Discovery

et al. 2022

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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.

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Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

Cited by 5 publications

References 88 publications

Advances in the genetic classification of amyotrophic lateral sclerosis

Advances in the genetic classification of amyotrophic lateral sclerosis

Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival

Progress in Amyotrophic Lateral Sclerosis Gene Discovery

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