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Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity
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Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity
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Journal Article
Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity
2024
Overview
Background
Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk.
Results
We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGS
HL
) and a biologically informed PGS for CIO (PGS
CIO
). The PGS
CIO
included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGS
CIO
demonstrated superior performance (
P
= 5.54 × 10
− 5
) relative to PGS
HL
(
P
= 2.93 × 10
− 3
). PGS
CIO
was also associated with CIO in our test cohort (
P
= 0.04), while the PGS
HL
did not show a significant association with CIO (
P
= 0.52).
Conclusion
This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.
Publisher
BioMed Central,Springer Nature B.V,BMC
Subject
/ Antineoplastic Agents - adverse effects
/ Biomedical and Life Sciences
/ Cisplatin-induced ototoxicity
/ Cochlea
/ Datasets
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Genomes
/ Genomics
/ Hearing Loss - chemically induced
/ Humans
/ Mice
/ Multifactorial Inheritance - genetics
/ Pharmacogenomics Beyond Single Common Genetic Variants
/ Polymorphism, Single Nucleotide - genetics
/ Single-nuclei RNA-sequencing
/ snRNA
