Role of DNA methylation in the relationship between glioma risk factors and glioma incidence: a two-step Mendelian randomization study.

in Scientific reports by Amy E Howell, Caroline Relton, Richard M Martin, Jie Zheng, Kathreena M Kurian

TLDR

  • A new study used genetic analysis to explore the link between DNA methylation and glioma risk, finding that changes in a specific region of the genome might be a risk factor for the disease.
  • Further research is needed to confirm these findings and understand the underlying mechanisms.

Abstract

Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR] < 0.05). Steiger filtering provided evidence against reverse causation. Colocalization presented evidence against genetic confounding and suggested that differential DNAm at the 3 CpG sites and glioma were driven by the same genetic variant. MR provided little evidence to suggest that DNAm acts as a mediator on the causal pathway between risk factors previously examined and glioma onset. To our knowledge, this is the first study to use MR to appraise the causal link of DNAm with glioma risk factors and glioma onset. Subsequent analyses are required to improve the robustness of our results and rule out horizontal pleiotropy.

Overview

  • The study aims to investigate the relationship between DNA methylation (DNAm) variation and glioma risk factors, as well as glioma incidence, using Mendelian randomization (MR) analysis.
  • The study uses data from a catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and a genome-wide association study of glioma risk (12,488 cases and 18,169 controls).
  • The primary objective is to identify the causal link between DNAm variation and glioma risk factors and glioma onset.

Comparative Analysis & Findings

  • MR evidence indicates that DNA methylation at three CpG sites (cg01561092, cg05926943, cg01584448) in the HEATR3 region is associated with glioma and glioblastoma risk (FDR < 0.05).
  • Steiger filtering and colocalization analyses suggest that the observed associations are not due to reverse causation or genetic confounding.
  • MR analysis provides little evidence to suggest that DNA methylation acts as a mediator on the causal pathway between previously examined risk factors and glioma onset.

Implications and Future Directions

  • The study's findings highlight the potential importance of HEATR3 region DNA methylation as a risk factor for glioma and glioblastoma.
  • Future studies are needed to improve the robustness of the results and rule out horizontal pleiotropy.
  • The study's approach can be applied to other complex diseases, and the results may have implications for the development of predictive biomarkers for glioma risk.
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