Dissecting Causal Pathways Using Mendelian Randomization with Summarized Genetic Data: Application to Age at Menarche and Risk of Breast Cancer.
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Abstract
Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms.
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A polygenic approach allows investigators to test for consistency of the causal finding across multiple variants that influence the exposure via different biological pathways.
“The latter approach allows investigators to test for consistency of the causal finding across multiple variants that influence the exposure via different biological pathways 61 .”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [61]
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- Authors
- Burgess, S., Thompson, D. J., Rees, J. M. B., Day, F. R., Perry, J. R., & Ong, K. K.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Burgess, Stephen
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-08-22
- Volume
- 207
- Issue
- 2
- Pages
- 481-487
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC5629317
- OpenAlex
- W2735339162
- Cited by
- 197
- References
- 36
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 29 · 2023: 28 · 2022: 26 · 2021: 30 · 2020: 30 · 2019: 16 · 2018: 11 · 2017: 1 · 2014: 1
- FWCI
- 10.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Breast Cancer Research Foundation (C5047/A10692, C5047/A15007, C1287/A10118, CA128978, W81XWH-10-1-0341, C5047/A8384, C1281/A12014, C12292/A11174, HEALTH-F2-2009-223175)
- Ovarian Cancer Research Fund (W81XWH-10-1-0341, C1281/A12014, C1287/A10118, C12292/A11174, CA128978, C5047/A10692, C5047/A15007, C5047/A8384, HEALTH-F2-2009-223175)
- McGill University
- Wellcome Trust (204623/Z/16/Z, 204623)
- Génome Québec
- Cancer Research UK (223175, C1281/A12014, C5047/A15007’, C1287‐A10118, 12014, HEALTHF2-2009-223175, C12292/A11174, ‘C5047/A10692, C1287, C5047/A8384, 10118, CA128978, C1287-A10710, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, W81XWH-10-1-0341, C1281)
- National Institute for Health and Care Research (NF-SI-0512-10165)
- British Heart Foundation (RG/08/014/24067)
- Royal Society (204623/Z/16/Z)
- European Commission (223175)
- National Institutes of Health (C1281/A12014, 223175, W81XWH-10-1-0341, C12292/A11174, W81XWH, C1287/A10118, C5047/A10692, HEALTH-F2-2009-223175, C5047/A15007, C5047/A8384, 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112)
- Canadian Institutes of Health Research (C5047/A8384, C5047/A15007, C5047/A10692, C1287/A10118, CA128978, C1281/A12014, C12292/A11174, W81XWH-10-1-0341, HEALTH-F2-2009-223175, 223175)
- Medical Research Council (MC_UU_12015/2, MR/L003120/1)
- National Cancer Institute (R01CA128978, U19CA148065, U19CA148537, U19CA148112)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- Mendelian randomization, multivariable Mendelian randomization, age at menarche, breast cancer risk, body mass index, mediation analysis, direct and indirect effects, unmeasured confounding, bidirectional effects, causal pathways
- MeSH terms
- Breast Neoplasms, Data Interpretation, Statistical, Female, Humans, Menarche, Models, Genetic, Body Mass Index, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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