The Polygenic Burden of Rare Variants Predicts Onset of CKD in the UK Biobank
Bibliographic record
Abstract
Background: Genetic contributors to chronic kidney disease (CKD) have been explored through monogenic mechanisms by rare mutations and polygenic mechanisms through the aggregate impact of many small-effect common variants. In this work, we test whether a polygenic burden of rare variants across numerous genes contributes to CKD by constructing a rare variant polygenic risk score (rvPRS). Methods: We first conducted a discovery exome-wide association study (ExWAS) of rare protein-truncating variants with a calculated severe CKD phenotype based on eGFR below 30 ml/min/1.73m2 using a discovery set of 834 cases and 147,855 British European controls in the UK Biobank (UKB). After excluding known Mendelian CKD genes, an rvPRS was constructed of 124 nominally significant (P<0.05) risk genes associated with severe CKD. As such, the effect conferred through rvPRS124 would not be driven through underlying monogenic mechanisms. We then tested the predictive power of rvPRS124 using a validation set consisting of 688 independent CKD events in the UKB. Results: In the validation set, rvPRS124 conferred a 21% increase in hazard for incident CKD onset with one rare protein-truncating allele (HR=1.21; 95%CI, 1.01-1.46; P=0.045) after adjusting for age, sex, the first 5 principal components of ancestry, and pertinent clinical risk factors including obesity, myocardial infarction, and smoking. Individuals with 2 or more rvPRS124 alleles (N=1,352) had a 10-fold increase in hazard for CKD onset compared to individuals with no rvPRS124 variants (HR=10.0, 95% CI, 2.5-39.4; P=1.3 x 10-3). No single gene in rvPRS124 replicated an association with CKD after adjusting for multiple hypothesis testing (P<4x10-4; 0.05/124), which emphasizes the importance of rare variant polygenic mechanisms underlying CKD. Lastly, through 1000 permutations of random gene sets, we show that the association of rvPRS124 with CKD was specific to the selected genes used to construct the score and not solely due to the gene count (P<0.05). Conclusions: Using the UKB, we demonstrate a cumulative impact of rare proteintruncating variants in genes not known to have monogenic effects on CKD. An omnigenic score, incorporating established clinical risk factors and both Monogenic and common variant polygenic effects, should also include the polygenic burden of rare variants in non-Mendelian CKD-related genes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.013 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 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".