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Systematic review of Mendelian randomization studies on risk of cancer.

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Markozannes, Georgios 
Kanellopoulou, Afroditi 
Dimopoulou, Olympia 
Kosmidis, Dimitrios 
Zhang, Xiaomeng 


BACKGROUND: We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. METHODS: We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. RESULTS: We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer. CONCLUSIONS: Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.



Cancer, Evidence grading, Mendelian randomization, Risk factors, Systematic review, Causality, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors

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BioMed Central
Wellcome Trust (204623/Z/16/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
British Heart Foundation (None)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)
This work was supported by Cancer Res UK (grant number C18281/A29019). SB is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ET is supported by a Cancer Res UK Career Development Fellowship (C31250/A22804). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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