Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations
Bibliographic record
Abstract
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear. METHODS: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status. FINDINGS: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood. INTERPRETATION: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival. FUNDING: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".