Are there causal relationships between ADHD and BMI? Evidence from multiple genetically informed designs

Background Attention-deficit/hyperactivity disorder (ADHD) and Body Mass Index (BMI) are associated. However, it remains unclear whether this association reflects causal relationships in either direction, or confounding. Here, we implemented genetically informed methods to examine bidirectional causality and potential confounding. Methods Three genetically informed methods were employed: (1) cross-lagged twin-differences analysis to assess bidirectional effects of ADHD symptoms and BMI at ages 8, 12, 14 and 16 years in 2,386 pairs of monozygotic twins from the Twins Early Development Study (TEDS), (2) within- and between-family ADHD and BMI polygenic score (PS) analysis in 3,320 pairs of dizygotic TEDS twins and (3) two-sample bidirectional Mendelian randomization (MR) using summary statistics from Genome-Wide Association Studies (GWAS) on ADHD (N=55,374) and BMI (N=806,834). Results Mixed results were obtained across the three methods. Twin-difference analyses provided little support for cross-lagged associations between ADHD symptoms and BMI over time. PS analyses were consistent with bidirectional relationships between ADHD and BMI with plausible time-varying effects from childhood to adolescence. MR findings were also consistent with bidirectional causal effects between ADHD and BMI. Multivariable MR suggested the presence of substantial confounding in bidirectional relationships. Conclusions The three methods converged to highlight multiple sources of confounding in the association between ADHD and BMI. PS and MR analyses suggested plausible causal relationships in both directions. Possible explanations for mixed causal findings across methods are discussed. Key messages Within-family polygenic score and Mendelian randomization analyses were consistent with bidirectional causal effects between ADHD and BMI. Findings: from different genetically informed methods suggested that multiple sources of confounding are at play, including genetic and shared environmental confounding, population stratification, assortative mating and dynastic effects. The ADHD polygenic score increasingly associated with BMI phenotype from childhood to adolescence, suggesting an increasing role of ADHD in the aetiology of BMI across the development. Conversely, BMI polygenic score association with ADHD phenotypes tended to decrease across the development. Addressing mixed evidence will require increased sample sizes to implement novel methods such as within-family MR.