Prioritization of candidate causal genes in GWAS signals of asthma in UK Biobank
Bibliographic record
Abstract
Abstract To identify susceptibility loci and candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS revealed 72 asthma-associated loci from 116 independent significant variants (PGWAS<5.0E-8). As expected, the yield of exonic variants associated with asthma was low, but nine were identified as potentially deleterious (CADD > 20) including a stop-gain mutation in the filaggrin (FLG) gene. The top lung TWAS gene on 17q12-q21 was GSDMB (PTWAS=1.42E-54). Other TWAS genes of interest include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). A novel risk locus was also revealed by the lung asthma TWAS on 1q23.3 with the putative gene encoding the gamma chain of the high-affinity IgE receptor (FCER1G, PTWAS=2.13E-6), which was also replicated in GTEx lung (PTWAS=3.71E-7). By testing a comprehensive set of cells and tissues, we then demonstrated that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants was in the blood. We mapped 485 eQTL-regulated genes associated with asthma in the blood and 50 of them were shown to be causally associated with asthma by Mendelian randomization. Prioritization of druggable genes revealed known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.
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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 | 0.004 | 0.019 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.004 | 0.005 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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".