Enhancer Dysregulation in ALS: Evidence for Noncoding Regulatory Mechanisms in Neuronal Inflammation and Apoptosis
Guillermo Pons Monnier1, Nerea Martin de Campo2, Miranda de la Pena-Tamez2, Oscar Gutierrez Trevino1, Emmanuel Martinez-Ledesma3, Raquel Cuevas-Diaz Duran2, Hector Martinez1
1Instituto de Neurología y Neurocirugía Hospital Zambrano Hellion, 2School of Medicine and Health Sciences, 3Institute for Obesity Research, Monterrey Institute of Technology and Higher Education
Objective:

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.

Background:

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. 

Design/Methods:

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.



Results:
We identified 690 LD-expanded ALS-associated SNPs, 145 of which overlapped enhancer-promoter regions. CDC42 emerged as the most recurrent target (n = 25). Sixty-two SNPs were predicted to alter TFB, affecting a total of 66 protein-coding genes. GSEA and PPI analyses revealed enrichment for immune and inflammatory pathways, including MHC class II antigen presentation (FDR =2.11×10-23), as well as gene sets associated with autoimmune disorders such as rheumatoid arthritis (FDR =5.22×10-14) and systemic lupus erythematosus (FDR=3.02×10-15). We identified 28 ALS-SNPs with eQTL evidence converging on 11 genes—including SLC9A8, C9orf72, -, HLA-DQA2, HLA-DOB, HLA-DRB1, SCFD1, and SUSD2—but GSEA and PPI of these genes did not yield statistically significant pathways.


Conclusions:

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.

10.1212/WNL.0000000000215211
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