Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

• Type of Material: Article
• Authors: Jonathan Glass, Emory University
• Language: English
• Date: 2021-12-06
• Publisher: Nature Research
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021, corrected publication 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-021-00973-1
• Title of Journal or Parent Work: NATURE GENETICS
• Volume: 53
• Issue: 12
• Start Page: 1636
• End Page: 1648
• Keywords: Neurodegenerative diseases; Motor neuron disease; Genome-wide association studies
• Research Categories: Biology, Neuroscience; Biology, Genetics

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.