Major Ethnic Populations Are Significantly Differentiated at the Glioblastoma Multiforme Candidate Loci

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with well-documented incidence disparities across ethnic populations: highest in Europeans and lowest in East Asians and Africans. Still, the genetic basis of these differences remains poorly understood. This study assessed whether population-level differences in GBM risk allele frequencies correlate with ethnic disparities in prevalence. We analyzed 673 genome-wide significant GBM candidate loci across five ethnic superpopulations and 26 subpopulations using phased genotype data from the 1000 Genomes Project Phase 3. Population genetic structure was characterized using allele frequencies, heterozygosity, Wright's fixation index, analysis of molecular variance (AMOVA), Nei's genetic distances, and principal coordinate analysis. Risk allele enrichment was visualized via hypergeometric heatmaps, and polygenic risk scores were compared using Kruskal-Wallis and Dunn's tests. Significant interpopulation differentiation was detected across all superpopulation pairs (p < 0.001). European populations had the highest polygenic risk scores, followed by South Asian and Admixed American populations, while East Asians had the lowest. Allele frequencies at key loci, including rs634537 (CDKN2B-AS1) and rs55705857 (CCDC26), differed up to tenfold. Finnish populations showed an elevated risk consistent with founder effects. Population genetic structure at GBM risk loci correlates with ethnic incidence disparities, underscoring the need for ancestry-specific approaches in risk modeling and trans-ancestry studies.