Dataset Information

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

ABSTRACT:

Background

The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors.

Methods

We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours.

Results

No significant associations (P < 1.58 × 10^-4) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10^-4 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (OR_SD = 3.91, P = 9.24 × 10^-3) and GBM (OR_SD = 4.86, P = 3.23 × 10^-2), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (OR_SD = 1.11, P = 1.39 × 10^-2 and OR_SD = 1.28, P = 1.73 × 10^-2, respectively), both associations being reliant on single genetic variants.

Conclusions

Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.

SUBMITTER: Saunders CN

PROVIDER: S-EPMC7852872 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

Saunders Charlie N CN Cornish Alex J AJ Kinnersley Ben B Law Philip J PJ Houlston Richard S RS

British journal of cancer 20201006 2

<h4>Background</h4>The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors.<h4>Methods</h4>We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weigh ...[more]

PMID: 33020596

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Project description:BackgroundAge at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner.MethodsWe conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations.ResultsOf the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null.ConclusionsThe genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Dataset Information

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

Background

Methods

Results

Conclusions

Publications

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

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