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Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.

Publication ,  Journal Article
Howell, AE; Robinson, JW; Wootton, RE; McAleenan, A; Tsavachidis, S; Ostrom, QT; Bondy, M; Armstrong, G; Relton, C; Haycock, P; Martin, RM ...
Published in: BMC Cancer
June 3, 2020

BACKGROUND: Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship. METHODS: We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset. RESULTS: Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding). CONCLUSIONS: Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.

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Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

June 3, 2020

Volume

20

Issue

1

Start / End Page

508

Location

England

Related Subject Headings

  • Triglycerides
  • Telomere Homeostasis
  • Risk Factors
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Obesity
  • Mendelian Randomization Analysis
  • Hypersensitivity
  • Humans
  • Glioma
 

Citation

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Howell, A. E., Robinson, J. W., Wootton, R. E., McAleenan, A., Tsavachidis, S., Ostrom, Q. T., … Kurian, K. M. (2020). Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study. BMC Cancer, 20(1), 508. https://doi.org/10.1186/s12885-020-06967-2
Howell, A. E., J. W. Robinson, R. E. Wootton, A. McAleenan, S. Tsavachidis, Q. T. Ostrom, M. Bondy, et al. “Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.BMC Cancer 20, no. 1 (June 3, 2020): 508. https://doi.org/10.1186/s12885-020-06967-2.
Howell AE, Robinson JW, Wootton RE, McAleenan A, Tsavachidis S, Ostrom QT, et al. Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study. BMC Cancer. 2020 Jun 3;20(1):508.
Howell, A. E., et al. “Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.BMC Cancer, vol. 20, no. 1, June 2020, p. 508. Pubmed, doi:10.1186/s12885-020-06967-2.
Howell AE, Robinson JW, Wootton RE, McAleenan A, Tsavachidis S, Ostrom QT, Bondy M, Armstrong G, Relton C, Haycock P, Martin RM, Zheng J, Kurian KM. Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study. BMC Cancer. 2020 Jun 3;20(1):508.
Journal cover image

Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

June 3, 2020

Volume

20

Issue

1

Start / End Page

508

Location

England

Related Subject Headings

  • Triglycerides
  • Telomere Homeostasis
  • Risk Factors
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Obesity
  • Mendelian Randomization Analysis
  • Hypersensitivity
  • Humans
  • Glioma