The relationship between BMI and COVID-19: exploring misclassification and selection bias in a two-sample Mendelian randomisation study
Authors: Clayton Gemma L , Gonçalves Soares Ana , Goulding Neil , Borges Maria Carolina , Holmes Michael V , Davey Smith George , Tilling Kate , Lawlor Deborah A , Carter Alice R 
Published: March 2022

AbstractObjectiveTo use the example of the effect of body mass index (BMI) on COVID-19 susceptibility and severity to illustrate methods to explore potential selection and misclassification bias in Mendelian randomisation (MR) of COVID-19 determinants.DesignTwo-sample MR analysis.SettingSummary statistics from the Genetic Investigation of ANthropometric Traits (GIANT) and COVID-19 Host Genetics Initiative (HGI) consortia.Participants681,275 participants in GIANT and more than 2.5 million people from the COVID-19 HGI consortia.ExposureGenetically instrumented BMI.Main outcome measuresSeven case/control definitions for SARS-CoV-2 infection and COVID-19 severity: very severe respiratory confirmed COVID-19 vs not hospitalised COVID-19 (A1) and vs population (those who were never tested, tested negative or had unknown testing status (A2)); hospitalised COVID-19 vs not hospitalised COVID-19 (B1) and vs population (B2); COVID-19 vs lab/self-reported negative (C1) and vs population (C2); and predicted COVID-19 from self-reported symptoms vs predicted or self-reported non-COVID-19 (D1).ResultsWith the exception of A1 comparison, genetically higher BMI was associated with higher odds of COVID-19 in all comparison groups, with odds ratios (OR) ranging from 1.11 (95%CI: 0.94, 1.32) for D1 to 1.57 (95%CI: 1.57 (1.39, 1.78) for A2. As a method to assess selection bias, we found no strong evidence of an effect of COVID-19 on BMI in a ‘no-relevance’ analysis, in which COVID-19 was considered the exposure, although measured after BMI. We found evidence of genetic correlation between COVID-19 outcomes and potential predictors of selection determined a priori (smoking, education, and income), which could either indicate selection bias or a causal pathway to infection. Results from multivariable MR adjusting for these predictors of selection yielded similar results to the main analysis, suggesting the latter.ConclusionsWe have proposed a set of analyses for exploring potential selection and misclassification bias in MR studies of risk factors for SARS-CoV-2 infection and COVID-19 and demonstrated this with an illustrative example. Although selection by socioeconomic position and arelated traits is present, MR results are not substantially affected by selection/misclassification bias in our example. We recommend the methods we demonstrate, and provide detailed analytic code for their use, are used in MR studies assessing risk factors for COVID-19, and other MR studies where such biases are likely in the available data.SummaryWhat is already known on this topic-Mendelian randomisation (MR) studies have been conducted to investigate the potential causal relationship between body mass index (BMI) and COVID-19 susceptibility and severity.-There are several sources of selection (e.g. when only subgroups with specific characteristics are tested or respond to study questionnaires) and misclassification (e.g. those not tested are assumed not to have COVID-19) that could bias MR studies of risk factors for COVID-19.-Previous MR studies have not explored how selection and misclassification bias in the underlying genome-wide association studies could bias MR results.What this study adds-Using the most recent release of the COVID-19 Host Genetics Initiative data (with data up to June 2021), we demonstrate a potential causal effect of BMI on susceptibility to detected SARS-CoV-2 infection and on severe COVID-19 disease, and that these results are unlikely to be substantially biased due to selection and misclassification.-This conclusion is based on no evidence of an effect of COVID-19 on BMI (a ‘no-relevance control’ study, as BMI was measured before the COVID-19 pandemic) and finding genetic correlation between predictors of selection (e.g. socioeconomic position) and COVID-19 for which multivariable MR supported a role in causing susceptibility to infection.-We recommend studies use the set of analyses demonstrated here in future MR studies of COVID-19 risk factors, or other examples where selection bias is likely.