Genome-wide pathway analysis in amyotrophic lateral sclerosis

Abstract

ABSTRACT. The aims of this study were to identify candidate singlenucleotide polymorphisms (SNPs) and mechanisms of amyotrophic lateral sclerosis (ALS) and to generate SNP-to-gene-to-pathway hypotheses. An ALS genome-wide association study (GWAS) dataset that included 483,051 SNPs in 276 patients with ALS and 271 controls of European descent was used in this study. Identify Candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 19 candidate SNPs, 8 genes, and 9 pathways, which provided 8 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs9352 alters the role of chromatin assembly factor 1 subunit A in the context of the pathways of chromatin and nucleosome assembly (nominal P < 0.001, false discovery rate (FDR) ≤ 0.001, 0.018, respectively). The second strongest was rs1046329 → HILS1 → chromatin assembly (nominal P < 0.001, FDR = 0.018). The third was rs11100790 → SMARCA5 → chromatin and nucleosome assembly (nominal P < 0.001, FDR ≤ 0.001, 0.018, respectively). The application of ICSNPathway analysis to the ALS GWAS dataset resulted in the identification of candidate SNPs, pathways, and biological mechanisms that might contribute to ALS susceptibility.

Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention

“…Given the prominence of the intensity and duration of the UPR for cell fate decisions under ER stress, ISWI/SMARCA5, whose RNA binding activity is conserved in Drosophila 53 and mammalian cells 54 , 55 , appears as a promising target for therapeutic intervention against the growing number of human diseases associated with ER stress and inappropriate UPR regulation 56 , 57 . Interestingly, GWA studies associated a SNP yielding a truncated mutant of human SMARCA5 to Amyotrophic lateral sclerosis 58 , a disease with multiple connections to ER stress and RNA metabolism 59 , 60 .…”