[P1–158]: IDENTIFICATION OF NOVEL GENETIC RISK VARIANTS FOR ALZHEIMER's DISEASE IN THE HMGCR GENE LOCUS
Bibliographic record
Abstract
Cholesterol lowering drugs inhibiting HMG-CoA reductase activity (statins) have been found to be protective in retrospective analyses of sporadic AD. Recently, a genetic variant in the HMGCR gene, also associated with reduced reductase activity, was found to be protective in AD (Leduc et al., 2015). This led us to systematically investigate all the genetic polymorphisms at the HMGCR locus with a population frequency greater than 5%, and their relationship to AD risk and HMGCR expression. Whole-genome sequencing, plasma, and cerebrospinal fluid (CSF) biomarker data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). Genetic polymorphisms in and around the HMGCR gene were extracted, and logistic regressions were performed in plink (pngu.mgh.harvard.edu) to identify variants associated with either risk or protection. Further analyses were performed in SPSS; Kaplan-Meier for conversion rate analysis, ANCOVA for expression analysis and Mann-Whitney U test for CSF biomarker analyses. We identified three new single nucleotide polymorphisms (SNPs) associated with marked increased risk of AD (ORs = 2.4 - 2.7, ps < 0.05), however only in subjects also positive for the APOE4 allele. Survival analysis further revealed that carriers of the risk alleles exhibit an accelerated conversion rate, but again only in APOE4 carriers (Xs > 6.6, ps < 0.01). HMGCR risk alleles were also associated with an increased gene expression in peripheral lymphocytes (Fs > 6.7, ps < 0.01); with no interaction with APOE4 status. Finally, a significant increase in CSF phospho-tau/tau ratio was observed in carriers of the risk alleles, specifically in APOE4 positive females (Us = 245.5, ps = 0.017), but not for Aβ levels. We have identified three new SNPs in the HMGCR locus associated with risk of AD, accelerated conversion rate to AD, and increased CSF phospho-tau/tau ratio, specifically in APOE4 carriers. In line with our hypothesis that protection is mediated by reduction in HMG-CoA reductase activity, the identified risk alleles were shown to be significantly associated with increased HMGCR expression. We are now in the process of replicating these findings in an independent cohort composed of autopsy-confirmed AD cases and age-matched controls from a population isolate form eastern Canada.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".