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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

Authors :
Klara Gawor
Sandra D'Alfonso
Nicholas Wood
Wouter Van Rheenen
Mark Bakker
Philip Van Damme
Christian Lunetta
Giancarlo Logroscino
Frederik Steyn
Joke Van Vugt
Anna Rapa
Alessandro Padovani
Maarten Kooyman
Olivier Bakker
Caroline Graff
John Landers
Paul Hop
David Whiteman
Johnathan Cooper-Knock
Lude Franke
Jonathan Mill
Julia Kraft
Luca Chiveri
Lukas Tittmann
Fleur Garton
Beben Benyamin
Elisabetta Pupillo
Patrick Deelen
Ramona Zwamborn
ALESSANDRA FERLINI
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

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. Across 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........3cf942ae05ca452af5f8bab40cc4f4ff
Full Text :
https://doi.org/10.1101/2021.03.12.21253159