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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.
- Source :
-
Nature genetics [Nat Genet] 2021 Dec; Vol. 53 (12), pp. 1636-1648. Date of Electronic Publication: 2021 Dec 06. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021. The Author(s).)
- Subjects :
- Amyotrophic Lateral Sclerosis metabolism
Brain metabolism
Cholesterol blood
Disease Progression
Female
Glutamine metabolism
Humans
Male
Mendelian Randomization Analysis
Microsatellite Repeats
Neurodegenerative Diseases genetics
Quantitative Trait Loci
RNA-Seq
Risk Factors
Amyotrophic Lateral Sclerosis genetics
Genome-Wide Association Study
Mutation
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 53
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 34873335
- Full Text :
- https://doi.org/10.1038/s41588-021-00973-1