Challenges at the <i>APOE</i> locus: A robust quality control approach for accurate <i>APOE</i> genotyping
Bibliographic record
Abstract
Abstract Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE *2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE . The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE *2/3/4 genotype quality. Here, we present a novel APOE *2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1,801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE . Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single- nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n=65,701). Primary analyses investigated AD risk in APOE *4/4 carriers. Additional supporting analyses were performed in APOE *3/4 and 3/3 strata. Outcomes were compared under two different APOE *2/3/4 filtering approaches Results Using more conventional APOE *2/3/4 filtering criteria (approach 1), we showed that, when in- phase with APOE *4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases certainty of the APOE *2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE *2/3/4.
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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 | 0.065 | 0.099 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.004 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".