A Transcriptome-Wide Association Study of Vestibular Schwannoma

Introduction: Vestibular schwannoma (VS) is currently managed with observation, radiation therapy, and microsurgery. While a genetic association with neurofibromatosis type II has been described, little is known about the causal genetic underpinnings of VS. A transcriptome-wide association study (TWAS), which tests the contribution of genetically determined gene expression to disease development, may shed light on biological mechanisms associated with VS.

Methods: We trained genetic models of gene expression using the Genotype-Tissue Expression (GTEx) Project reference transcriptome data. Using the United Kingdom Biobank (UKBB; n ~ 500,000), we conducted TWAS to identify gene-level associations with VS. We employed our group’s Joint-Tissue Imputation TWAS methodology (Zhou D et al, Nature Genetics 2020) in a case–control design. Mendelian randomization (MR) was then implemented to test for the gene causal effects on the tumor phenotype. Results from the UKBB were then validated in BioVU, the United States’ largest single-institution DNA biobank (n ~ 110,000) linked to electronic health records.

Results: We identified 63 novel genes with genetically-determined expression associations (p < 0.0001) with VS. HERC6, HIST2H2AC, AC243772.2, DNPH1, and RNF25 were found to have the most significant associations with VS. DNPH1 has been previously shown to be significantly associated with tinnitus, suggesting the importance of the gene in the pathophysiology of VS-associated tinnitus.

Conclusion: Identified genes were found to be predictive of the vestibular schwannoma phenotype. Notably, these genes may account for the known comorbidities of the phenotype. The findings of this study provide new avenues for the development of targeted therapies for vestibular schwannoma ([Fig. 1]).

Fig. 1:

Publikationsverlauf

Artikel online veröffentlicht:
05. Februar 2024