Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.
Amyotrophic Lateral Sclerosis
/ genetics
Brain
/ metabolism
Cholesterol
/ blood
Disease Progression
Female
Genome-Wide Association Study
Glutamine
/ metabolism
Humans
Male
Mendelian Randomization Analysis
Microsatellite Repeats
Mutation
Neurodegenerative Diseases
/ genetics
Neurons
/ metabolism
Quantitative Trait Loci
RNA-Seq
Risk Factors
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
12
03
2021
accepted:
18
10
2021
entrez:
7
12
2021
pubmed:
8
12
2021
medline:
29
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34873335
doi: 10.1038/s41588-021-00973-1
pii: 10.1038/s41588-021-00973-1
pmc: PMC8648564
doi:
Substances chimiques
Glutamine
0RH81L854J
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Meta-Analysis
Langues
eng
Sous-ensembles de citation
IM
Pagination
1636-1648Subventions
Organisme : Medical Research Council
ID : MC_UU_00011/4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K01417X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L501529/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R56 NS073873
Pays : United States
Organisme : Medical Research Council
ID : G1001253
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L501542/1
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : ALCHALABI-TALBOT/APR14/926-794
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : ALCHALABI-DOBSON/APR14/829-791
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_G1000733
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0500289
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L021803/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900635
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : SMITH/APR16/847-791
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17115
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-0907
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-060-0003-RG-SMITH
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS073873
Pays : United States
Organisme : Parkinson's UK
ID : G-1307
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0600974
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R024804/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J004758/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100695
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : SHAW/NOV14/985-797
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Motor Neurone Disease Association
ID : SHAW/APR15/970-797
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900688
Pays : United Kingdom
Investigateurs
Giancarlo Comi
(G)
Nilo Riva
(N)
Christian Lunetta
(C)
Francesca Gerardi
(F)
Maria Sofia Cotelli
(MS)
Fabrizio Rinaldi
(F)
Luca Chiveri
(L)
Maria Cristina Guaita
(MC)
Patrizia Perrone
(P)
Mauro Ceroni
(M)
Luca Diamanti
(L)
Carlo Ferrarese
(C)
Lucio Tremolizzo
(L)
Maria Luisa Delodovici
(ML)
Giorgio Bono
(G)
Antonio Canosa
(A)
Umberto Manera
(U)
Rosario Vasta
(R)
Alessandro Bombaci
(A)
Federico Casale
(F)
Giuseppe Fuda
(G)
Paolina Salamone
(P)
Barbara Iazzolino
(B)
Laura Peotta
(L)
Paolo Cugnasco
(P)
Giovanni De Marco
(G)
Maria Claudia Torrieri
(MC)
Francesca Palumbo
(F)
Salvatore Gallone
(S)
Marco Barberis
(M)
Luca Sbaiz
(L)
Salvatore Gentile
(S)
Alessandro Mauro
(A)
Letizia Mazzini
(L)
Fabiola De Marchi
(F)
Lucia Corrado
(L)
Sandra D'Alfonso
(S)
Antonio Bertolotto
(A)
Maurizio Gionco
(M)
Daniela Leotta
(D)
Enrico Odddenino
(E)
Daniele Imperiale
(D)
Roberto Cavallo
(R)
Pietro Pignatta
(P)
Marco De Mattei
(M)
Claudio Geda
(C)
Diego Maria Papurello
(DM)
Graziano Gusmaroli
(G)
Cristoforo Comi
(C)
Carmelo Labate
(C)
Luigi Ruiz
(L)
Delfina Ferrandi
(D)
Eugenia Rota
(E)
Marco Aguggia
(M)
Nicoletta Di Vito
(N)
Piero Meineri
(P)
Paolo Ghiglione
(P)
Nicola Launaro
(N)
Michele Dotta
(M)
Alessia Di Sapio
(A)
Guido Giardini
(G)
Cinzia Tiloca
(C)
Silvia Peverelli
(S)
Franco Taroni
(F)
Viviana Pensato
(V)
Barbara Castellotti
(B)
Giacomo P Comi
(GP)
Roberto Del Bo
(R)
Mauro Ceroni
(M)
Stella Gagliardi
(S)
Lucia Corrado
(L)
Letizia Mazzini
(L)
Flavia Raggi
(F)
Costanza Simoncini
(C)
Annalisa Lo Gerfo
(A)
Maurizio Inghilleri
(M)
Alessandra Ferlini
(A)
Isabella L Simone
(IL)
Bruno Passarella
(B)
Vito Guerra
(V)
Stefano Zoccolella
(S)
Cecilia Nozzoli
(C)
Ciro Mundi
(C)
Maurizio Leone
(M)
Michele Zarrelli
(M)
Filippo Tamma
(F)
Francesco Valluzzi
(F)
Gianluigi Calabrese
(G)
Giovanni Boero
(G)
Augusto Rini
(A)
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Type : CommentIn
Informations de copyright
© 2021. The Author(s).
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