Genome-wide association study (GWAS) of cisplatin-related hearing loss in testicular cancer survivors (TCS) to reveal associated variant in Wolfram syndrome 1 (WFS1) gene.
Bibliographic record
Abstract
10015 Background: Cisplatin is widely used and highly ototoxic; we sought to identify genetic variants that modulate cisplatin-related hearing loss. Methods: We performed a GWAS for cisplatin-related hearing loss in 512 patients of European genetic ancestry enrolled in an ongoing multi-center North American clinical study of TCS. The geometric mean of air conduction thresholds measured at 4, 6, 8, 10 and 12 kHz was the quantitative phenotype used in the GWAS. SNPs were genotyped on the Illumina HumanOmniExpressExome chip and imputed using the 1000 Genomes reference panel, with 5.1 million SNPs passing quality control for GWAS inclusion. Covariates included in the GWAS were age at audiometry, cumulative cisplatin dose, and 10 genotypic principal components. Results: One SNP, rs62283056, in the first intron of WFS1 met genome-wide significance for association with cisplatin-associated hearing loss (P = 4.8 x 10-9). Mutations in this gene can cause autosomal dominant deafness and Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). The minor allele of rs62283056 (frequency 0.21 in the GWAS cohort) associates with increased hearing loss and decreased expression of WFS1 (cis-eQTL) in several human tissues from the GTEx Project, including cerebellar hemisphere, tibial nerve and thyroid. WFS1 is differentially expressed in the human inner ear (cochlea vs. vestibule, Padj = 0.032, Schrauwen et al. Hear Res 2015). We found a significant interaction between rs62283056 genotype and cumulative cisplatin dose (P = 0.029), indicating higher dose may exacerbate the hearing loss effect in patients carrying the minor allele. When hearing loss is dichotomized as a geometric mean > 20 dB (n = 242 affected), the allelic OR for hearing loss risk is 1.9 [95% CI: 1.3 – 2.8]. Conclusions: The WFS1 SNP is the first report of a genome-wide significant association with cisplatin-related hearing loss in adults. Expression data and known gene function corroborate its potential involvement in hearing loss. Future studies will focus on replicating and extending the genetic and mechanistic findings discovered here.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".