Deciphering the 8q24.21 association for glioma.

in Human molecular genetics by Victor Enciso-Mora, Fay J Hosking, Ben Kinnersley, Yufei Wang, Sanjay Shete, Diana Zelenika, Peter Broderick, Ahmed Idbaih, Jean-Yves Delattre, Khe Hoang-Xuan, Yannick Marie, Anna Luisa Di Stefano, Marianne Labussière, Sara Dobbins, Blandine Boisselier, Pietro Ciccarino, Marta Rossetto, Georgina Armstrong, Yanhong Liu, Konstantinos Gousias, Johannes Schramm, Ching Lau, Sarah J Hepworth, Konstantin Strauch, Martina Müller-Nurasyid, Stefan Schreiber, Andre Franke, Susanne Moebus, Lewin Eisele, Asta Forsti, Kari Hemminki, Ian P Tomlinson, Anthony Swerdlow, Mark Lathrop, Matthias Simon, Melissa Bondy, Marc Sanson, Richard S Houlston

TLDR

  • A fine-mapping study identified a low-frequency SNP rs55705857 associated with non-glioblastoma multiforme (non-GBM) glioma risk, with a pooled odds ratio of 4.3 (P = 2.31 × 10(-94)).

Abstract

We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.

Overview

  • The study aimed to fine-map the location of a previously identified tagSNP at 8q24.21 associated with glioma risk using data from four genome-wide association studies.
  • The study used imputation genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals to improve marker density across the 700 kb region.
  • The primary objective of the study was to identify the functional basis of the 8q24.21 association and explore its relationship to glioma subtype.

Comparative Analysis & Findings

  • The study found an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) to be sufficient to fully capture the 8q24.21 association.
  • The association with rs55705857 was confined to non-glioblastoma multiforme (non-GBM) tumours, with a pooled odds ratio for low-grade glioma of 4.3 (P = 2.31 × 10(-94)).
  • The non-GBM association was validated in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)).

Implications and Future Directions

  • These findings provide additional insights into the aetiological basis of glioma development and may lead to the identification of new therapeutic targets.
  • Future studies could explore the functional significance of rs55705857 and its relationship to the CCDC26 long non-coding RNA.
  • The study highlights the importance of fine-mapping associations to identify the underlying functional mechanisms and improve our understanding of complex diseases.
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