Abstract 4143772: Genome wide association study meta-analysis of 19,487 individuals with mitral valve prolapse identifies 52 novel genomic regions and highlights pro-fibrosis genes
Bibliographic record
Abstract
Introduction: Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is estimated to affect between 1-3% of the general population. A subset of individuals with MVP develop malignant arrhythmias, often in the context of myocardial fibrosis. The genetics of MVP, and genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood. Methods: We defined MVP using a combination of claims data and echocardiographic diagnosis across 15 cohorts spanning 5 countries and performed a meta-analysis of genome-wide association studies (GWAS) for MVP including 19,487 MVP cases among 2,247,054 individuals. Causal genes were prioritized using a combination of methods including the identification of variants in active promoters/enhancers using mitral valve ATAC-seq data from an external dataset. To determine whether prioritized genes may be differentially expressed in myocardial fibrosis, we compared single-cell RNA sequencing between fibrosed papillary muscles and normal left ventricular among two individuals with severe MVP. Results: There were 67 unique genome-wide significant (GWS; p<5x10 -8 ) genomic regions, of which 52 were novel. Of these, 38 GWS regions included either missense variants or variants overlapping a promoter active in valve tissue as suggested by mitral valve ATAC-seq data. Pathway analysis of prioritized genes highlighted etiological roles for extracellular matrix and cardiomyocyte biology. 33 prioritized genes were differentially expressed between fibrotic papillary muscle tissue and normal left ventricle, the majority of which were specific to cardiomyocytes. One of these genes, CAMK2D , was also observed as sub-GWS in a recent GWAS of myocardial interstitial fibrosis and has notable pleiotropy for arrhythmia traits including atrial fibrillation and atrioventricular block. Conclusions: We performed the largest GWAS of MVP to-date, discovering 52 novel GWS regions, and prioritized genes relevant to myocardial fibrosis, an important risk factor for adverse outcomes among individuals with MVP.
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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 | 0.004 | 0.007 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.016 |
| Bibliometrics | 0.002 | 0.005 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".