201 ARFRP1 in the Amygdala Predicts Glioma in Transcriptome-Wide Association Study

INTRODUCTION: Gliomas are the most common primary malignant brain tumor in adults. Genome-wide association studies (GWAS) have identified 25 loci associated with glioma risk. Using transcriptome-wide association study (TWAS) methodology with joint-tissue imputation, our group investigated 3 genetic repositories to identify genes predictive of the glioma phenotype using the Glioma International Case Control Study (GICC), the Gliomascan GWAS, and the UK Biobank. METHODS: We characterized the genetic basis of glioma by performing a GWAS using de-identified patient data from these 3 databases in a case-controlled design. For each GWAS, we performed a TWAS utilizing the PrediXcan framework in parallel to identify associations between genetically predicted gene expression in glioma. We applied 59 gene expression prediction models trained on data from GTEx and enriched via joint-tissue imputation (JTI) which borrows information across different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. We used a r2 threshold of 0.1 for expression prediction. Bonferroni correction was used for multiple testing adjustment. RESULTS: 7094 cases of glioma and 427,814 controls were included in our meta-analysis. Notably, 12 genes were found to be significantly associated with the glioma phenotype in the Gliomscan database and 17 genes in the GICC database. From the JTI analysis, TERT upregulation in the nucleus accumbens and substantia nigra were found to be significantly associated with the glioma phenotype. Furthermore, ARFRP1 in the amygdala was highly predictive of the glioma phenotype. CONCLUSIONS: Glioma is a genetically complex diagnosis with generally poor prognosis. Several novel genes were identified as being predictive of the glioma phenotype. JTI identified several genes including TERT, ARFRP1, and ZGPAT within the nucleus accumbens, substantia nigra, and amygdala predicting glioma. These genes provide further avenues for precision medicine in glioma and targets for therapy.