Genome-Wide Association Studies of a Composite Renal Phenotype Reveal Pleiotropic Effects and a Novel Locus
Bibliographic record
Abstract
Background: Our previous genome-wide association study (GWAS) of hematuria using ICD codes in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Hematuria cases had higher systolic blood pressure, higher urine albumin:creatinine (uACR) ratios and lower eGFR compared to controls, supporting enrichment for hematuria due to glomerular pathologies. Although most GWAS analyze one trait at a time, many clinical syndromes are defined by combinations of outcomes. Therefore, generating a combined phenotype may improve power to detect loci influencing multiple traits. Methods: The composite outcome of hematuria and albuminuria was chosen to enrich for glomerular disease. We performed a case-control GWAS in the white British subset of the UK Biobank. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR >3 mg/mmol. Controls did not have either an ICD code for hematuria nor an uACR >3 mg/mmol. Results: 2,429 cases and 343,509 controls were included. eGFR was significantly lower in cases (F: 88.6±16.5 mL/min/1.72m2, M: 82.2±20.1 mL/min/1.72m2 by CKD EPI) compared to controls (F: 90.6±13.1 mL/min/1.72m2, M: 90.6±12.6 mL/min/1.72m2) in both sexes. Variants at 4 loci met genome-wide significance (p<5x10-8) with the following nearest genes: COL4A4-COL4A3, TRIM27, ETV1 and CUBN. TRIM27 is part of the extended MHC locus. Our previous GWAS of hematuria reported COL4A3-COL4A3 variants and HLA-B*0801 within MHC, but the latter is not in linkage disequilibrium (LD) with the TRIM27 variant. Additional loci are identified for the composite outcome including CUBN (previously associated with albuminuria) and a novel signal at chromosome 7 (ETV1, (nearest gene), rs146676616, p=1.3x10-8, alternate allele (G) frequency in cases versus controls: 1.77% versus 0.91%, OR=2.61, 95% CI=1.87-3.63). Conclusions: GWAS for the composite outcome of hematuria and albuminuria identifies 4 loci. Three were not identified in our previous GWAS of hematuria enriched for glomerular causes. These include variants with closest genes TRIM27, within the extended MHC locus but not in LD with HLA-B*0801 reported previously, CUBN and a novel signal at chromosome 7. Analysis of composite phenotypes has the potential to identify novel loci which have pleiotropic effects. Funding: Government Support - Non-U.S.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".