A transcriptome-wide association study identifies <i>PALMD</i> as a susceptibility gene for calcific aortic valve stenosis
Bibliographic record
Abstract
Abstract Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease with no drug that can stop or delay its progression. Elucidating the genetic factors underpinning CAVS is an urgent priority to find new therapeutic targets 1 . Major landmarks in genetics of CAVS include the discoveries of NOTCH1 2 and LPA 3 . However, genetic variants in these genes accounted for a small number of cases and low population-attributable risk. Here we mapped a new susceptibility locus for CAVS on chromosome 1p21.2 and identified PALMD (palmdelphin) as the causal gene. PALMD was revealed using a transcriptome-wide association study (TWAS) 4 , which combines a genome-wide association study (GWAS) of 1,009 cases and 1,017 ethnically-matched controls with the first large-scale expression quantitative trait loci (eQTL) mapping study on human aortic valve tissues (n=233). The CAVS risk alleles and increasing disease severity were both associated with lowered mRNA expression levels of PALMD in valve tissues. The top variant explained up to 12.5% of the population-attributable risk and showed similar effect and strong association with CAVS (P=1.53 × 10 −10 ) in UK Biobank comparing 1,391 cases and 352,195 controls. The identification of PALMD as a susceptibility gene for CAVS provides new insights about the genetic nature of this disease and opens new avenues to investigate its etiology and develop much-needed therapeutic options.
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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 | 0.000 | 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 | 0.001 | 0.001 |
| 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".