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Multi-ancestry geno...
Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
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- Foss-Skiftesvik, Jon (author)
- Department of Neurosurgery, Rigshospitalet University Hospital, Copenhagen, Denmark; Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark; Section for Neonatal Genetics, Statens Serum Institute, Copenhagen, Denmark
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- Li, Shaobo (author)
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, CA, Los Angeles, United States
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- Rosenbaum, Adam (author)
- Umeå universitet,Onkologi
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- Munch Hagen, Christian (author)
- Section for Neonatal Genetics, Statens Serum Institute, Copenhagen, Denmark
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- Stoltze, Ulrik Kristoffer (author)
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark; Department of Clinical Genetics, Rigshospitalet University Hospital, Copenhagen, Denmark
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- Ljungqvist, Sally (author)
- Umeå universitet,Onkologi
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- Hjalmars, Ulf (author)
- Umeå universitet,Onkologi
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- Schmiegelow, Kjeld (author)
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark
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- Morimoto, Libby (author)
- Center for Personalized Medicine, Children's Hospital of Los Angeles, CA, Los Angeles, United States
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- de Smith, Adam J. (author)
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, CA, Los Angeles, United States
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- Mathiasen, René (author)
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet University Hospital, Copenhagen, Denmark
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- Metayer, Catherine (author)
- School of Public Health, University of California, CA, Berkeley, United States
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- Hougaard, David (author)
- Section for Neonatal Genetics, Statens Serum Institute, Copenhagen, Denmark
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- Melin, Beatrice S. (author)
- Umeå universitet,Onkologi
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- Walsh, Kyle M. (author)
- Division of Neuro-Epidemiology, Department of Neurosurgery, Duke University, NC, Durham, United States
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- Bybjerg-Grauholm, Jonas (author)
- Section for Neonatal Genetics, Statens Serum Institute, Copenhagen, Denmark
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- Dahlin, Anna M., 1979- (author)
- Umeå universitet,Onkologi
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- Wiemels, Joseph L. (author)
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, CA, Los Angeles, United States
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(creator_code:org_t)
- 2023-02-22
- 2023
- English.
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In: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 25:9, s. 1709-1720
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- Childhood brain tumors
- genetic susceptibility
- glioma
- GWAS
- pediatric neuro-oncology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Foss-Skiftesvik, ...
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Li, Shaobo
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Rosenbaum, Adam
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Munch Hagen, Chr ...
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Stoltze, Ulrik K ...
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Ljungqvist, Sall ...
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show more...
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Hjalmars, Ulf
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Schmiegelow, Kje ...
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Morimoto, Libby
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de Smith, Adam J ...
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Mathiasen, René
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Metayer, Catheri ...
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Hougaard, David
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Melin, Beatrice ...
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Walsh, Kyle M.
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Bybjerg-Grauholm ...
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Dahlin, Anna M., ...
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Wiemels, Joseph ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Neuro-Oncology
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Umeå University