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S109: TRANSCRIPTOME WIDE ASSOCIATION AND SINGLE-CELL RNASEQ ANALYSIS IDENTIFIES 7 NOVEL GENES IN VESTIBULAR SCHWANNOMA TUMORS
Robert J Dambrino, MD, MPH¹; Candace Grisham²; Ruiqu Zhou³; Frederic A Vallejo, MD, MS⁴; Phillip Lin⁵; Reid C Thompson, MD⁴; Peter J Morone, MD, MSCI⁴; Taha Jan, MD³; Eric R Gamazon, PhD⁵; ¹University of Pittsburgh Medical Center, Department of Neurological Surgery; ²Vanderbilt University School of Medicine; ³Vanderbilt University Medical Center, Department of Otolaryngology - Head and Neck Surgery; ⁴Vanderbilt University Medical Center, Department of Neurological Surgery; ⁵Vanderbilt University Medical Center, Division of Genetic Medicine

Introduction: Vestibular schwannoma (VS) is an intracranial nerve sheath neoplasm currently treated 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, Vanderbilt University’s DNA biobank (n ~ 250,000) linked to electronic health records. Independent validation of TWAS linked genes was performed using single cell RNA sequencing (scRNA-seq) of vestibular schwannoma tumor samples.

Results: We identified 10 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 relevance of this gene in the pathophysiology of VS-associated tinnitus. 7 out of the 10 identified genes were found to be expressed at the transcriptomic level using scRNA-seq data from vestibular schwannoma samples.

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. 7 of these genes were found in vestibular schwannoma tumor samples at the transcriptomic level. The findings of this study provide new avenues for the development of targeted therapies for vestibular schwannoma.

 

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