Region-Based Analyses of Existing Genome-Wide Association Studies Identifies Novel Potential Genetic Susceptibility Regions for Glioma

Abstract

Glioma is a rare and debilitating brain cancer with one of the lowest cancer survival rates. Genome-wide association studies have identified 34 genetic susceptibility regions. We sought to discover novel susceptibility regions using approaches that test groups of contiguous genetic markers simultaneously. We analyzed data from three independent glioma studies of European ancestry, GliomaScan (1,316 cases/ 1,293 controls), Australian Genomics and Clinical Outcomes of Glioma Consortium (560 cases/2,237 controls), and Glioma International Case-Control Study (4,000 cases/2,411 controls), using the machine learning algorithm DEPendency of association on the number of Top Hits and a region-based regression method based on the generalized Berk?Jones (GBJ) statistic, to assess the association of glioma with genomic regions by glioma type and sex. Summary statistics from the UCSF/Mayo Clinic study were used for independent validation. We conducted a meta-analysis using GliomaScan, Australian Genomics and Clinical Outcomes of Glioma Consortium, Glioma International Case-Control Study, and UCSF/Mayo. We identified 11 novel candidate genomic regions for glioma risk common to multiple studies. Two of the 11 regions, 16p13.3 containing RBFOX1 and 1p36.21 containing PRDM2, were significantly associated with female and male glioma risk respectively, based on the results of the meta-analysis. Both regions have been previously linked to glioma tumor progression. Three of the 11 regions contain neurotransmitter receptor genes (7q31.33 GRM8, 5q35.2 DRD1, and 15q13.3 CHRNA7). Our region-based approach identified 11 genomic regions that suggest an association with glioma risk of which two regions, 16p13.3 and 1p36.21, warrant further investigation as genetic susceptibility regions for female and male risk, respectively. Our analyses suggest that genetic susceptibility to glioma may differ by sex and highlight the possibility that synapse-related genes play a role in glioma susceptibility. �2024 The Authors.