Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that has significant overlap with frontotemporal dementia (FTD). Mutations in specific genes have been identified that can cause and/or predispose patients to ALS. However, the clinical variability seen in ALS patients suggests that additional genes impact pathology, susceptibility, severity, and/or progression of the disease. To identify molecular pathways involved in ALS, we undertook a meta-analysis of published genetic modifiers both in patients and in model organisms, and undertook bioinformatic pathway analysis. From 72 published studies, we generated a list of 946 genes whose perturbation (1) impacted ALS in patient populations, (2) altered defects in laboratory models, or (3) modified defects caused by ALS gene ortholog loss of function. Herein, these are all called modifier genes. We found 727 modifier genes that encode proteins with human orthologs. Of these, 43 modifier genes were identified as modifiers of more than one ALS gene/model, consistent with the hypothesis that shared genes and pathways may underlie ALS. Further, we used a gene ontology-based bioinformatic analysis to identify pathways and associated genes that may be important in ALS. To our knowledge this is the first comprehensive survey of ALS modifier genes. This work suggests that shared molecular mechanisms may underlie pathology caused by different ALS disease genes. Surprisingly, few ALS modifier genes have been tested in more than one disease model. Understanding genes that modify ALS-associated defects will help to elucidate the molecular pathways that underlie ALS and provide additional targets for therapeutic intervention.

Motor Neuron Susceptibility in ALS/FTD

“…Similarly, other genes highly expressed in vulnerable MNs are implicated in their susceptibility to degeneration, such as semaphorin A3 (Sema A3) and matrix metalloproteinase 9 (MMP-9) (see section “Neuroprotective and Neurotoxic Factor Expression in MN Subpopulations” below). Recently, a comprehensive bioinformatics meta-analysis of ALS modifier genes was performed from 72 published studies (Yanagi et al, 2019). A total of 946 modifier genes were identified and of these, 43 genes were identified as modifiers in more than one ALS gene/model.…”

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

“…On the other hand, in remaining susceptibility loci, pathogenic variants have not been reported yet [ 21 ]. Nonetheless, the genotyping of the tagging SNPs identified (which are quite common in the general population) might play an important role in the near future in clinical trials and prognostic counseling [ 22 ]; Another category of genes and loci efficiently detected by association studies are those acting as ALS phenotype modifiers, showing in a few cases an overlap with Mendelian genes and susceptibility genetic factors [ 23 ]. At present, the mutational screening of “modifier” genes would have little or no impact in a diagnostic setting; A final group of genes, often listed among those someway related to ALS, is constituted by genes coding for certain proteins, which play important roles in ALS pathogenesis, but in which no causative variant has been previously identified.…”

“…Another category of genes and loci efficiently detected by association studies are those acting as ALS phenotype modifiers, showing in a few cases an overlap with Mendelian genes and susceptibility genetic factors [ 23 ]. At present, the mutational screening of “modifier” genes would have little or no impact in a diagnostic setting;…”

From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline

“…The remaining percentage of patients with genetic forms of the pathologies is characterized by a high degree of genetic heterogeneity both at allele and at locus level [17,229]. Furthermore, several risk factors and genetic modifiers able to increase susceptibility to the diseases, or to influence the rate of progression have now been identified [17,230]. In conclusion, the two diseases represent a pathological "continuum" possibly associated with a complex inheritance and influenced by an important interplay between genetic risks and likely environmental factors.…”