Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
20
07
2020
accepted:
20
11
2020
entrez:
1
2
2021
pubmed:
2
2
2021
medline:
19
4
2022
Statut:
epublish
Résumé
Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (
Identifiants
pubmed: 33523907
pii: 7/3/eabd9036
doi: 10.1126/sciadv.abd9036
pmc: PMC7810371
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NEI NIH HHS
ID : R01 EY016482
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA093459
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA133996
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS073873
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000949
Pays : United States
Organisme : NIDA NIH HHS
ID : P50 DA019706
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA NS003154
Pays : United States
Organisme : NHLBI NIH HHS
ID : R37 HL039693
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004446
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA013324
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA026141
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA089392
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA006908
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097007
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA004212
Pays : United States
Organisme : NEI NIH HHS
ID : N01 EY02127
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136725
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES011740
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 ES101986
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL053941
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS073873
Pays : United States
Organisme : Medical Research Council
ID : MR/N008324/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL039693
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY016514
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL070100
Pays : United States
Organisme : NIA NIH HHS
ID : N01 AG050002
Pays : United States
Organisme : NCI NIH HHS
ID : K05 CA124911
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA084724
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL49869
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA009532
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL076784
Pays : United States
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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