Command Palette

Search for a command to run...

Preprint WatchMildSeptember 21st, 2026

Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk

Zhao T, Hoffman MM, Wu G, Belzil VV.

Genetically predicted blood DNA methylation and gene expression at C9orf72 are associated with ALS risk (Bonferroni-significant CpGs and TWAS signal), implicating inherited regulatory variation at the C9orf72 locus in disease susceptibility.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

A medRxiv methylome-wide association study (Zhao et al.) applied genetically predicted blood DNA methylation models to ALS GWAS summary statistics from 27,205 cases and 110,881 controls and found convergent methylation and expression signals at C9orf72 after Bonferroni correction. That adds regulatory weight to C9orf72 as a causal locus beyond the hexanucleotide repeat expansion. It bears on one Claidex failure, wve-004-c9orf72-als-ftd-phase1-2-translational-mismatch, where Wave's variant-selective antisense oligonucleotide halved cerebrospinal fluid poly-GP without changing any clinical outcome. The preprint does not test transcript knockdown and concerns inherited regulatory variation in mostly sporadic disease, so it strengthens target relevance while leaving open the question that sank WVE-004: whether lowering repeat-containing transcripts is the lever that moves progression. Severity is MILD because the single matching claim is a translational mismatch, not an efficacy failure.

Abstract excerpt

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and underlying molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study (MWAS) of genetically predicted blood DNA methylation using the PrediXcan framework. CpG-specific prediction models developed in the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. In total, genetically predicted methylation at 192,378 unique CpG sites was evaluated using S-PrediXcan. At a nominal threshold of p < 0.05, 3,741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significantly associated with ALS risk. These included signals near established ALS and ALS-frontotemporal dementia genes and loci, including C9orf72, TBK1, SCFD1, and MOB3B, as well as three CpGs mapping to WHAMM at 15q25.2, a region not previously implicated in ALS by GWAS. Predicted methylation was positively associated with ALS risk at 18 CpGs and inversely associated at seven. Complementary transcriptome-wide association analyses using GTEx v8 whole-blood gene-expression prediction models identified 11 genes associated with ALS risk after Bonferroni correction, including convergent methylation and expression signals at C9orf72. These findings add a regulatory dimension to ALS genetic studies by prioritizing CpG sites, genes, and genomic regions through which inherited variation may influence disease susceptibility. PrediXcan-based MWAS therefore provides a complementary strategy for refining genetic association signals into biologically testable candidates and identifying regulatory mechanisms for further functional investigation.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.