Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification
Bibliographic record
Abstract
The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".