MPS 01-02 GENOME WIDE HOMOZYGOSITY ANALYSIS - ASSOCIATION WITH CORONARY ARTERY DISEASE AND GENE EXPRESSION IN MONOCYTES AND MACROPHAGES
Bibliographic record
Abstract
Objective: Homozygosity mapping is a strategy with a potential to identify and quantify the recessive component of inheritance - long stretches (usually >1Mb) of consecutive homozygous genotypes are known as runs of homozygosity (ROHs). A comprehensive analysis was undertaken regarding the contribution of ROHs to the genetic architecture of coronary artery disease (CAD) and regulation of gene expression in monocytes and macrophages. Design and Method: Approximately 2.5 million single nucleotide polymorphisms (SNPs) from previously conducted genome-wide association (GWA) studies in 12,123 individuals with CAD and 12,197 CAD-free controls from 11 European populations were used to explore differences in the genetic architecture of homozygosity between the two groups. Consensus ROHs overlapping across studies were identified and their relevance to CAD was examined individually and at the aggregate level. Finally, we combined genome-wide consensus ROHs with data from monocyte and macrophage transcriptome profiling in the Cardiogenics study to explore whether the presence of ROHs was related to expression of genes that map to specific ROHs. Results: Individuals with CAD had approximately 0.63 (95% CI: 0.4–0.8, P = 1.49 × 10−9) excess of ROHs when compared to CAD-free controls. The average total length of ROHs was approximately 1046.92 kb (95% CI: 634.4–1459.5, P = 6.61 × 10−7) greater in individuals with CAD than control subjects. Overlapping consensus ROHs favouring increased risk of CAD were much more common than those showing the opposite direction of association with CAD (P = 2.69 × 10−33). Subjects with ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. Conclusions: This study provides evidence for an excess of homozygosity in CAD and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis. Our data suggest that recessive variants may be an important factor in the genetic architecture of CAD.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".