Examining risk factors for weight change during midlife: A Mendelian randomization study

Background Maintaining a healthy weight across adulthood reduces morbidity and mortality risk in later life. This study aimed to examine factors contributing to weight change over a one-year interval in midlife. While conventional epidemiological analyses have reported risk factors associated with weight change, biases such as confounding present challenges when inferring causality. Methods Conventional observational analyses were used in addition to a one-sample Mendelian randomization (MR) approach to estimate the genetically predicted effects of four exposures (alcohol consumption, smoking intensity, educational attainment and Alzheimer’s disease liability) on weight change (mean age: 56.9 years) using data from 329 531 participants in the UK Biobank. Results One-sample MR indicated strong evidence that Alzheimer’s disease liability increased the odds of weight loss whilst conventional analyses reported little evidence of this. In MR and conventional epidemiological analyses, higher educational attainment was associated with maintaining a steady weight. In addition, higher alcohol consumption was associated with weight gain in conventional analyses only. Finally, whilst conventional analyses showed that smoking heaviness was associated with weight gain, the converse was supported by MR, which indicated strong evidence that smoking heaviness reduced the odds of weight gain. Conclusions Our findings highlight important risk factors for weight change in midlife and emphasise the public health importance of evaluating the dynamic changes to body weight within a causal inference setting. ### Competing Interest Statement Tom G. Richardson is an employee of GlaxoSmithKline outside of this work. All other authors declare no competing interests. ### Funding Statement This work was in part supported by the MRC Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol [MC\_UU\_00011/1]. Davey Smith conducts research at the National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Power is supported by the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff, and Exeter from the Medical Research Council /UK Research and Innovation [MR/N0137941/1]. Richardson was a UK Research and Innovation Research Fellow while contributing to this study [MR/S003886/1]. Tyrell is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK [SBF004\1079]. Fang is supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology [108902/Z/15/Z]. Gkatzionis is supported by the UK Medical Research Council and the University of Bristol [MC\_UU\_00011/3]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data were obtained from the UKBB study, who have obtained ethics approval from the Research Ethics Committee (REC; approval number: 11/NW/0382) and informed consent from all participants enrolled in UKBB. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are all available from within the supplementary materials or publicly accessible from the resources cited. * BMI : Body mass index CI : Confidence interval IPW : Inverse Probability Weighting MR : Mendelian randomization OR : Odds ratio