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

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.

LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies

“…The LAG3 transcripts are non-detectable in all 34 distinct cell types, including multiple excitatory and inhibitory neurons, oligodendrocytes (ODC), oligodendrocyte precursor cells (OPCs) microglia (MGL), astrocytes (AST), or endothelial cells (EC). Cluster markers as detailed in Saez-Atienzar et al 2021. As the inability to detect LAG3 in human neuronal samples seemed to contradict previous observations (Mao et al, 2016), we analyzed LAG3 expression in mouse brains. Prior RNAseq data reported that Lag3 is poorly expressed in both hippocampus and cerebellum of WT mice (Liu et al, 2018), and likely absent in murine neurons (Zhang et al, 2014).…”

“…The LAG3 transcripts are non-detectable in all 34 distinct cell types, including multiple excitatory and inhibitory neurons, oligodendrocytes (ODC), oligodendrocyte precursor cells (OPCs) microglia (MGL), astrocytes (AST), or endothelial cells (EC). Cluster markers as detailed in Saez-Atienzar et al 2021. this version posted April 26, 2021 ; https://doi.org/10.1101/2021.04.25.441302 doi: bioRxiv preprint…”

“…Single nuclei RNA sequencing (snRNAseq) analysis of human frontal cortex was completed as previously described (Saez-Atienzar et al, 2021). In brief, frozen frontal cortex tissue samples from 16 donors in the North American Brain Expression Consortium study series (dbGaP Study Accession: phs001300.v1.p1, (Myers et al, 2007)) were obtained from the University of Maryland Brain and Tissue Bank through the NIH NeuroBioBank.…”

Polygenic Score Models for Alzheimer’s Disease: From Research to Clinical Applications

“…Furthermore, the application of polygenic score models can help refine the results of genetic analyses based on control cohorts (i.e., controls in whom the disease of interest has not been investigated in detail) by ruling out individuals at risk of developing diseases (Escott-Price et al, 2019a). Moreover, polygenic score models may be used to define an individual's risk of having a specific neurodegenerative disease, as studies have demonstrated that such models (or the genotyping of specific variants) can predict the risk of Parkinson's disease (Nalls et al, 2016), Huntington's disease (Kremer et al, 1994), amyotrophic lateral sclerosis (Saez-Atienzar et al, 2021), and multiple sclerosis (The International Multiple Sclerosis Genetics Consortium (IMSGC), 2010). In addition, polygenic score models may help estimate the effects of aging on disease risk.…”

Genetic and Transcriptomic Biomarkers in Neurodegenerative Diseases: Current Situation and the Road Ahead

“…Although numerous cellular processes have been implicated in ALS—including membrane trafficking, excitotoxicity, signal transduction, nucleocytoplasmic transport, and neuron projection morphogenesis, among others [ 78 , 79 , 80 ], the mechanisms that underlie the disease are uncertain. As a result, there has been less progress made towards the diagnosis and treatment of ALS compared to other neurodegenerative diseases.…”