SHROOM3 Expression and CKD: A Mendelian Randomization Analysis
Bibliographic record
Abstract
Background: Genome-wide association studies (GWAS) identified common genetic variants within 100 kilobases of the transcription start site of SHROOM3 individually associated with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (uACR). This upstream region contains regulatory elements, and the location of these variants suggests that altered SHROOM3 expression could be the mechanism underlying the observed associations. We sought to evaluate if a genetically predicted decrease in SHROOM3 expression was associated with an increased risk of CKD. Methods: First, we found genetic variants associated with SHROOM3 expression, known as expression quantitative trait loci (eQTL), by conducting a meta-analysis of 7408 genetic variants from 51 tissue datasets from the public Human Kidney eQTL Atlas, GTEx, and NephQTL resources. Independent eQTL variants were then selected to be used in a two-sample Mendelian randomization analysis. Using European ancestry summary-level GWAS results from the CKDGen Consortium, UK Biobank, and the Finnish Genetics Consortium, we compared the effect of each variant on SHROOM3 expression to its effect on risk of CKD (n = 480,698), baseline cross-sectional eGFR (n = 1,201,929), previously defined decline in eGFR phenotypes “Rapid3” or “CKDi25” (n = 141,964), and uACR (n = 547,361). Results: We identified 50 independent genetic variants associated with SHROOM3 expression (P < 0.05, r2 < 0.01). These variants cumulatively explained 2% of the variability in SHROOM3 expression. A 34% reduction in genetically predicted SHROOM3 expression was associated with a 0.3% (95% CI: 0.1% - 0.5%) reduction in cross-sectional eGFR (P = 0.002). There was no association between genetically predicted SHROOM3 expression and CKD, longitudinal rapid decline in eGFR, or uACR (P > 0.05). Conclusions: Mendelian randomization analysis suggests a small reduction in genetically predicted SHROOM3 expression throughout life is associated with a slightly lower baseline eGFR. In a seeming contradiction, we did not find that lower genetically predicted SHROOM3 expression was associated with the presence of CKD, rapid decline in eGFR, nor uACR. These results are consistent with recent reports that genetic association with cross-sectional eGFR, maximum attained eGFR, longitudinal decline in eGFR, and risk of CKD may differ. Funding: Private Foundation Support
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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 | 0.051 | 0.054 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.015 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.002 | 0.002 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.004 | 0.002 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.010 | 0.001 |
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".