RT Journal Article
T1 Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.
A1 Saez-Atienzar, Sara
A1 Bandres-Ciga, Sara
A1 Langston, Rebekah G
A1 Kim, Jonggeol J
A1 Choi, Shing Wan
A1 Reynolds, Regina H
A1 Abramzon, Yevgeniya
A1 Dewan, Ramita
A1 Ahmed, Sarah
A1 Landers, John E
A1 Chia, Ruth
A1 Ryten, Mina
A1 Cookson, Mark R
A1 Nalls, Michael A
A1 Chiò, Adriano
A1 Traynor, Bryan J
K1 Amyotrophic Lateral Sclerosis
K1 Genetic Testing
K1 Genome-Wide Association Study
K1 Humans
K1 Polymorphism, Single Nucleotide
AB 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 (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.
PB Public Library of Science
YR 2020
FD 2020-11-20
LK http://hdl.handle.net/10668/17080
UL http://hdl.handle.net/10668/17080
LA en
NO Saez-Atienzar S, Bandres-Ciga S, Langston RG, Kim JJ, Choi SW, Reynolds RH, et al. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci Adv. 2021 Jan 15;7(3):eabd9036.
DS RISalud
RD Apr 7, 2025