Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

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.

Automated summary

Despite progress in genetic research on ALS, the molecular mechanisms of the disease remain not fully understood. A study involving genome-wide data and polygenic risk score approach identified key biological pathways and cell types related to ALS, revealing themes like neuron projection morphogenesis and signal transduction. The findings suggest that genetic risk in ALS is consistently linked to certain types of neurons and oligodendrocytes, and certain genes may play a role in the disease. The study concludes that diverse genetic causes of ALS converge on a smaller number of common pathways and cell types.