Saez-Atienzar, SaraBandres-Ciga, SaraLangston, Rebekah GKim, Jonggeol JChoi, Shing WanReynolds, Regina HAbramzon, YevgeniyaDewan, RamitaAhmed, SarahLanders, John EChia, RuthRyten, MinaCookson, Mark RNalls, Michael AChiò, AdrianoTraynor, Bryan J2023-02-092023-02-092020-11-20Saez-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.http://hdl.handle.net/10668/17080Despite 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.enAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/Amyotrophic Lateral SclerosisGenetic TestingGenome-Wide Association StudyHumansPolymorphism, Single NucleotideMAP-kinase-activated kinase 3Genetic Risk ScoreAmyotrophic Lateral SclerosisRibonucleotidesMendelian Randomization AnalysisRNA-SeqSignal TransductionGenomicsMorphogenesisOligodendrogliaresearch article33523907open accessAnálisis de la aleatorizaciónMendelianaEsclerosis amiotrófica lateralFosfotransferasasGenómicaMorfogénesisOligodendroglíaPuntuación de riesgo genéticoRNA-SeqRibonucleótidosTransducción de señal10.1126/sciadv.abd90362375-2548PMC7810371https://europepmc.org/articles/pmc7810371?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810371/pdf