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

Amy E Howell; Caroline L Relton; Richard M Martin; Jie Zheng; Kathreena M Kurian

doi:10.1038/s41598-023-33621-1

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

Amy E Howell, Caroline L Relton, Richard M Martin, Jie Zheng^*, Kathreena M Kurian^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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.

Original language	English
Article number	6590 (2023)
Number of pages	15
Journal	Scientific Reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-33621-1
Publication status	Published - 21 Apr 2023

Bibliographical note

Funding Information:
We would like to thank the GoDMC and the authors from the meta-analysed glioma GWAS (UK, French, German, MDA, UCSF-SFAGS, GliomaScan, GICC and UCSF/Mayo) for allowing us to access the summary statistics for this analysis.

Funding Information:
AHE and KKM were supported by the Brain Tumour Bank and Research Fund, Southmead hospital charity (Charity Registration Number:1055900). RMM and CR are supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A29019) and the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research and is a partnership between University Hospitals Bristol NHS Trust, Weston NHS Foundation Trust and the University of Bristol. RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care.

Publisher Copyright:
© 2023, The Author(s).

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Utilising multi-omic epidemiology approaches to better understand the molecular pathways underpinning glioma onset.
Author: Howell, A. E., 9 May 2023
Supervisor: Kurian, K. (Supervisor), Zheng, J. (Supervisor), Relton, C. (Supervisor), Martin, R. (Supervisor), Yarmolinsky, J. (Supervisor) & Haycock, P. C. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

File

Cite this

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

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.",

author = "Howell, {Amy E} and Relton, {Caroline L} and Martin, {Richard M} and Jie Zheng and Kurian, {Kathreena M}",

note = "Funding Information: We would like to thank the GoDMC and the authors from the meta-analysed glioma GWAS (UK, French, German, MDA, UCSF-SFAGS, GliomaScan, GICC and UCSF/Mayo) for allowing us to access the summary statistics for this analysis. Funding Information: AHE and KKM were supported by the Brain Tumour Bank and Research Fund, Southmead hospital charity (Charity Registration Number:1055900). RMM and CR are supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A29019) and the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research and is a partnership between University Hospitals Bristol NHS Trust, Weston NHS Foundation Trust and the University of Bristol. RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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AU - Kurian, Kathreena M

N1 - Funding Information: We would like to thank the GoDMC and the authors from the meta-analysed glioma GWAS (UK, French, German, MDA, UCSF-SFAGS, GliomaScan, GICC and UCSF/Mayo) for allowing us to access the summary statistics for this analysis. Funding Information: AHE and KKM were supported by the Brain Tumour Bank and Research Fund, Southmead hospital charity (Charity Registration Number:1055900). RMM and CR are supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A29019) and the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research and is a partnership between University Hospitals Bristol NHS Trust, Weston NHS Foundation Trust and the University of Bristol. RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. Publisher Copyright: © 2023, The Author(s).

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N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

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Utilising multi-omic epidemiology approaches to better understand the molecular pathways underpinning glioma onset.

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