Systematic review of Mendelian randomization studies on risk of cancer

Georgios Markozannes, Afroditi Kanellopoulou, Olympia Dimopoulou, Dimitrios Kosmidis, Xiaomeng Zhang, Lijuan Wang, Evropi Theodoratou, Dipender Gill, Stephen Burgess, Konstantinos K Tsilidis*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish
Article number41
JournalBMC Medicine
Volume20
Issue number1
DOIs
Publication statusPublished - 2 Feb 2022

Keywords

  • Causality
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Ovarian Neoplasms
  • Polymorphism, Single Nucleotide
  • Risk Factors

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