P2‐173: Mutation Analysis of the <i>MS4A</i> and <i>TREM</i> Gene‐Clusters in a Case‐Control Alzheimer's Disease Dataset
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Bibliographic record
Abstract
Genetic studies identified an association between Alzheimer's disease (AD) and common polymorphisms in the MS4A and TREM loci, each containing cluster of homologous genes. We searched for rare coding variants in 15 genes mapped to these loci by next generation sequencing of a North American dataset (210 cases and 233 controls). Analysis of the MS4A gene-cluster revealed loss-of-function variants in 6 controls and 3 cases. Investigation of the TREM gene-cluster detected known AD associated TREM2 substitutions (p.R47H, p.D87N and p.H157Y) affecting both TREM2 isoforms (NM_018965 and NM_001271821). We also identified two cases with novel TREM2 variants (p.L205P and p.G219C), which mapped only to the isoform NM_001271821. A p.S248R substitution in the homologous TREML2 gene was detected in 5 controls and 1 case suggesting a protective effect (pooled p-value = 0.033). Our study advocates for the importance of mutation analysis of controls, particularly for GWAS loci containing SNPs with a minor allele frequency higher in controls versus cases (e.g. MS4A locus), to search for functional variants with a protective effect.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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 it