RT Journal Article SR Electronic T1 Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study JF RMD Open JO RMD Open FD EULAR SP e003633 DO 10.1136/rmdopen-2023-003633 VO 9 IS 4 A1 Freuer, Dennis A1 Meisinger, Christa YR 2023 UL http://rmdopen.bmj.com/content/9/4/e003633.abstract AB Background Based on Barker’s hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis.Methods Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR.Results Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI.Conclusion Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.Data are available in a public, open access repository. All analyses based on summary statistics from genome-wide association studies publicly available at the following resources. Data on birth weight and childhood BMI have been downloaded from www.egg-consortium.org. RA-GWAS summary statistics were downloaded from GRASP (the Genome-Wide Repository of Associations Between SNPs and Phenotypes) https://grasp.nhlbi.nih.gov/FullResults.aspx. Summary-level data for multiple sclerosis was accessed via the OpenGWAS database API 62 63. The psoriasis datasets were obtained from the 6th release of the FinnGen consortium (https://www.finngen.fi/en/access_results). Summary-level data for BMI in adulthood were taken from https://zenodo.org/record/1251813%23.XxgQ2J5KiUl.