UMMS Affiliation

Department of Neurology

Publication Date

2021-01-15

Document Type

Article

Disciplines

Genetics and Genomics | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology

Abstract

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.

Keywords

amyotrophic lateral sclerosis, ALS, genetics

Rights and Permissions

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). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

DOI of Published Version

10.1126/sciadv.abd9036

Source

Saez-Atienzar S, Bandres-Ciga S, Langston RG, Kim JJ, Choi SW, Reynolds RH; International ALS Genomics Consortium; ITALSGEN, Abramzon Y, Dewan R, Ahmed S, Landers JE, Chia R, Ryten M, Cookson MR, Nalls MA, Chiò A, Traynor BJ. Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types. Sci Adv. 2021 Jan 15;7(3):eabd9036. doi: 10.1126/sciadv.abd9036. PMID: 33523907; PMCID: PMC7810371. Link to article on publisher's site

Journal/Book/Conference Title

Science advances

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33523907

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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