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Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci

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  • Jon Foss-Skiftesvik, University Hospital Rigshospitalet, Copenhagen, Denmark., Statens Serum Institut
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  • Christian Munch Hagen, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., University of Copenhagen, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • René Mathiasen, Rigshospitalet University Hospital
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  • Dea Adamsen, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Marie Bækvad-Hansen, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Anders D Børglum
  • Merete Nordentoft, University of Copenhagen, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Thomas Werge, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, University of Copenhagen, Mental Health Centre Sct. Hans, Roskilde, Denmark
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  • Michael Christiansen, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Kjeld Schmiegelow, Rigshospitalet University Hospital, University of Copenhagen
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  • Marianne Juhler, University of Copenhagen, University Hospital Rigshospitalet, Copenhagen, Denmark.
  • ,
  • Preben Bo Mortensen
  • David Michael Hougaard, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Jonas Bybjerg-Grauholm, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark., iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research

INTRODUCTION: Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease.

METHOD: A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls.

RESULTS: For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10-7 and 9.668 × 10-8, respectively). PAPPA2 regulates local bioavailability of insulin-like growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10-7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors.

DISCUSSION: This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways.

Original languageEnglish
JournalChild's Nervous System
Volume37
Issue3
Pages (from-to)819–830
Number of pages12
ISSN0256-7040
DOIs
Publication statusPublished - Mar 2021

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