학술논문
Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
Document Type
article
Author
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
Source
Neuro-Oncology. 25(9)
Subject
Language
Abstract
BackgroundAlthough 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.MethodsMeta-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.ResultsCommon 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).ConclusionsIn 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.