Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence

Mendelian randomization analyses are often performed using summarized data. The causal estimate from a one‐sample analysis (in which data are taken from a single data source) with weak instrumental variables is biased in the direction of the observational association between the risk factor and outcome, whereas the estimate from a two‐sample analysis (in which data on the risk factor and outcome are taken from non‐overlapping datasets) is less biased and any bias is in the direction of the null. When using genetic consortia that have partially overlapping sets of participants, the direction and extent of bias are uncertain. In this paper, we perform simulation studies to investigate the magnitude of bias and Type 1 error rate inflation arising from sample overlap. We consider both a continuous outcome and a case‐control setting with a binary outcome. For a continuous outcome, bias due to sample overlap is a linear function of the proportion of overlap between the samples. So, in the case of a null causal effect, if the relative bias of the one‐sample instrumental variable estimate is 10% (corresponding to an F parameter of 10), then the relative bias with 50% sample overlap is 5%, and with 30% sample overlap is 3%. In a case‐control setting, if risk factor measurements are only included for the control participants, unbiased estimates are obtained even in a one‐sample setting. However, if risk factor data on both control and case participants are used, then bias is similar with a binary outcome as with a continuous outcome. Consortia releasing publicly available data on the associations of genetic variants with continuous risk factors should provide estimates that exclude case participants from case‐control samples.

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.

IMPORTANCE Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. OBJECTIVE To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. DESIGN, SETTING, AND PARTICIPANTS The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021.