Disentangling the direct and indirect effects of childhood adiposity on type 1 diabetes and immune-associated diseases: a multivariable Mendelian randomization study

Abstract Background The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). However, robust causal evidence supporting this claim has been extremely challenging to uncover, particularly given the typical early onset of T1D. Methods In this study, we used genetic variation to separate the direct effect of childhood body size on T1D risk from the effects of body size at different stages in the life course using univariable and multivariable Mendelian randomization (MR). Similar MR analyses were conducted on risk of seven other chronic immune-associated diseases. Findings Childhood body size provided evidence of an effect on T1D (based on a sample of 5,913 cases and 8,282 controls) using a univariable model (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remained after accounting for body size at birth and during adulthood (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). The direct effect of childhood body size was validated using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also obtained evidence that childhood adiposity influences risk of asthma (OR=1.31, 95% CI=1.08 to 1.60, P=0.007), eczema (OR=1.25, 95% CI=1.03 to 1.51, P=0.024) and hypothyroidism (OR=1.42, 95% CI=1.12 to 1.80, P=0.004). However, these estimates all attenuated to the null when accounting for adult body size, suggesting that the effect of childhood adiposity on these outcomes is mediated by adiposity in later life. Interpretation Our findings support a causal role for higher childhood adiposity on higher risk of being diagnosed with T1D. In contrast, the effect of childhood adiposity on the other immune-associated diseases studied was explained by a long-term effect of remaining overweight for many years over the life course.