Dataset Information

Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study.

ABSTRACT:

Background

Only a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer.

Methods

We conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from the UKB study (n = 194,174) and summary-level genetic outcome associations from the Breast Cancer Association Consortium (n = 228,951). Our exposures included all 34 biochemical biomarkers in the UKB, and our outcomes were overall, oestrogen-positive, and oestrogen-negative breast cancer. We performed inverse-variance weighted MR, weighted median MR, MR-Egger, and MR-PRESSO for 30 biomarkers for which we found multiple instrumental variables. We additionally performed multivariable MR to adjust for known risk factors, bidirectional MR to investigate reverse causation, and MR Bayesian model averaging to rank the significant biomarkers by their genetic evidence.

Results

Increased genetic liability to overall breast cancer was robustly associated with the following biomarkers by decreasing importance: testosterone (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.04-1.21), high-density lipoprotein (HDL) cholesterol (OR: 1.08, 95% CI: 1.04-1.13), insulin-like growth factor 1 (OR: 1.08, 95% CI: 1.02-1.13), and alkaline phosphatase (ALP) (OR: 0.93, 95% CI: 0.89-0.98).

Conclusions

Our findings support a likely causal role of genetically predicted levels of testosterone, HDL cholesterol, and IGF-1, as well as a novel potential role of ALP in breast cancer aetiology. Further studies are needed to understand full disease pathways that may inform breast cancer prevention.

SUBMITTER: Tang SN

PROVIDER: S-EPMC9685978 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study.

Tang Sonja N SN Zuber Verena V Tsilidis Konstantinos K KK

BMC medicine 20221123 1

<h4>Background</h4>Only a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer.<h4>Methods</h4>We conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from th ...[more]

PMID: 36424572

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Project description:ObjectiveTo examine whether sleep traits have a causal effect on risk of breast cancer.DesignMendelian randomisation study.SettingUK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.Participants156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis.ExposuresSelf reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.Main outcome measureBreast cancer diagnosis.ResultsIn multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.ConclusionsFindings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.

Project description:ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Dataset Information

Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study.

Background

Methods

Results

Conclusions

Publications

Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study.

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