Bibliographic record
Abstract
Background and objectives Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy. Design, setting, participants, & measurements We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 ( COL4A4 - COL4A3 ) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed HLA haplotypes. Results In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05–21.33] versus 12.12 mg/g [7.61–19.29]; P <0.001; men: 8.85 mg/g [5.66–16.19] versus 7.52 mg/g [5.04–12.39]; P <0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m 2 ; P <0.001; men: 87±15 versus 90±13 ml/min per 1.72 m 2 ; P <0.001), supporting enrichment of glomerular hematuria. Variants at six loci ( PDPN , COL4A4-COL4A3 , HLA-B , SORL1 , PLLP , and TGFB1 ) met genome-wide significance ( P <5E-8). At chromosome 2, COL4A4 p.Ser969X (rs35138315; minor allele frequency=0.00035; P <7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: COL4A3 p.Gly695Arg (rs200287952; minor allele frequency=0.00021; P <2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common COL4A4 intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; P <2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the HLA haplotypes, HLA-B ( *0801 ; minor allele frequency=0.14; P <4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: PDPN , SORL1 , and PLLP ). Conclusions Our study identifies six loci associated with hematuria, including independent variants in COL4A4 - COL4A3 and HLA-B . Additionally, three novel loci are reported, including an association with an intronic variant in PDPN expressed in the podocyte. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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".