To determine whether single nucleotide polymorphisms (SNPs) associated with amyotrophic lateral sclerosis (ALS) and located within active enhancer regions contribute to genetic dysregulation and neuronal cell death.

Enhancers are cis-regulatory elements that modulate gene expression and can act over long genomic distances. SNPs within enhancer–promoter regions can disrupt transcription factor binding (TFB), leading to widespread transcriptional dysregulation of target genes. With the majority of ALS-SNPs located within noncoding genetic regions, there is a need to investigate their potential effect on cis-regulatory elements. 

ALS-associated SNPs were retrieved from the NHGRI-EBI GWAS Catalog. We expanded our dataset to include variants in high linkage disequilibrium (LD) and identified variants overlapping enhancer-promoter regions with a high probability of disrupting TFB. We cross-referenced predicted target genes with expression quantitative trait loci (eQTL) data from neuronal tissue to assess their effect on gene expression. Finally, we performed gene set enrichment analysis (GSEA) and constructed protein–protein interaction (PPI) networks to identify convergent biological pathways associated with these ALS-SNPs.

ALS-SNPs overlapping enhancer regions were predicted to disrupt TFB in immune and inflammatory genes. However, there is yet insufficient evidence that disrupted enhancer-promoter regions drive disease onset.