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...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02660-2 |
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| author | Sonja N. Tang Verena Zuber Konstantinos K. Tsilidis |
| author_facet | Sonja N. Tang Verena Zuber Konstantinos K. Tsilidis |
| author_sort | Sonja N. Tang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T07:38:55Z |
| format | Article |
| id | doaj.art-d6ecdc1388534ee381a88fcb1061d4a6 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T07:38:55Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-d6ecdc1388534ee381a88fcb1061d4a62022-12-22T04:36:39ZengBMCBMC Medicine1741-70152022-11-0120111410.1186/s12916-022-02660-2Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation studySonja N. Tang0Verena Zuber1Konstantinos K. Tsilidis2Department of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonAbstract 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.https://doi.org/10.1186/s12916-022-02660-2Mendelian randomisationBreast cancerBiomarkersInstrumental variablesCausal inferenceEpidemiology |
| spellingShingle | Sonja N. Tang Verena Zuber Konstantinos K. Tsilidis Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study BMC Medicine Mendelian randomisation Breast cancer Biomarkers Instrumental variables Causal inference Epidemiology |
| title | Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study |
| title_full | Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study |
| title_fullStr | Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study |
| title_full_unstemmed | Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study |
| title_short | Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study |
| title_sort | identifying and ranking causal biochemical biomarkers for breast cancer a mendelian randomisation study |
| topic | Mendelian randomisation Breast cancer Biomarkers Instrumental variables Causal inference Epidemiology |
| url | https://doi.org/10.1186/s12916-022-02660-2 |
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