Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 25; no. 9; pp. 1709 - 1720
• Main Authors: Foss-Skiftesvik, Jon, Li, Shaobo, Rosenbaum, Adam, Hagen, Christian Munch, Stoltze, Ulrik Kristoffer, Ljungqvist, Sally, Hjalmars, Ulf, Schmiegelow, Kjeld, Morimoto, Libby, de Smith, Adam J, Mathiasen, René, Metayer, Catherine, Hougaard, David, Melin, Beatrice, Walsh, Kyle M, Bybjerg-Grauholm, Jonas, Dahlin, Anna M, Wiemels, Joseph L
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 05.09.2023
• Subjects: Childhood brain tumors; genetic susceptibility; glioma; GWAS; Pediatric Neuro-Oncology; Childhood brain tumors; glioma; GWAS; genetic susceptibility; pediatric neuro-oncology
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/noad042

Abstract Background Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. Methods Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case–control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. Results Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179–1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). Conclusions In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.