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

Jon Foss-Skiftesvik; Shaobo Li; Adam Rosenbaum; Christian Munch Hagen; Ulrik Kristoffer Stoltze; Sally Ljungqvist; Ulf Hjalmars; Kjeld Schmiegelow; Libby Morimoto; Adam J de Smith; René Mathiasen; Catherine Metayer; David Hougaard; Beatrice Melin; Kyle M Walsh; Jonas Bybjerg-Grauholm; Anna M Dahlin; Joseph L Wiemels

doi:10.1093/neuonc/noad042

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

Neuro Oncol. 2023 Sep 5;25(9):1709-1720. doi: 10.1093/neuonc/noad042.

Authors

Jon Foss-Skiftesvik^{1

2

3}, Shaobo Li⁴, Adam Rosenbaum⁵, Christian Munch Hagen³, Ulrik Kristoffer Stoltze^{2

6}, Sally Ljungqvist⁵, Ulf Hjalmars⁵, Kjeld Schmiegelow², Libby Morimoto⁷, Adam J de Smith⁴, René Mathiasen², Catherine Metayer⁸, David Hougaard³, Beatrice Melin⁵, Kyle M Walsh⁹, Jonas Bybjerg-Grauholm³, Anna M Dahlin⁵, Joseph L Wiemels⁴

Affiliations

¹ Department of Neurosurgery, Rigshospitalet University Hospital, Copenhagen, Denmark.
² Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark.
³ Section for Neonatal Genetics, Statens Serum Institute, Copenhagen, Denmark.
⁴ Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
⁵ Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
⁶ Department of Clinical Genetics, Rigshospitalet University Hospital, Copenhagen, Denmark.
⁷ Center for Personalized Medicine, Children's Hospital of Los Angeles, Los Angeles, California, USA.
⁸ School of Public Health, University of California, Berkeley, Berkeley, California, USA.
⁹ Division of Neuro-Epidemiology, Department of Neurosurgery, Duke University, Durham, North Carolina, USA.

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.

Keywords: Childhood brain tumors; GWAS; genetic susceptibility; glioma; pediatric neuro-oncology.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Astrocytoma* / genetics
Child
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Glioma* / genetics
Humans
Polymorphism, Single Nucleotide
RNA, Long Noncoding*

Substances

RNA, Long Noncoding

Abstract

Publication types

MeSH terms

Substances

Grants and funding