The causal effects of body mass index (BMI) on childhood symptoms of depression, anxiety disorder, and attention-deficit hyperactivity disorder: a within family Mendelian randomization study

Hughes, A. M.; Morris, T. T.; Ayorech, Z.; Tesli, M.; Ask, H.; Reichborn-Kjennerud, T.; Andreassen, O. A.; Magnus, P.; Helgeland, O.; Johansson, S.; Njolstad, P. R.; Davey Smith, G.; Havdahl, A.; Howe, L. D.; Davies, N. M.

Abstract Objectives: Higher BMI in childhood predicts neurodevelopmental and emotional problems, but it is unclear if these associations are causal. Previous genetic studies imply causal effects of childhood BMI on depression and attention-deficit hyperactivity disorder (ADHD), but these observations might also reflect effects of demography and the family environment. We used within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype, to investigate the impact of BMI on symptoms of depression, anxiety, and ADHD symptoms at age 8. Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). Participants were 26,370 8-year-old children (48.7% female) born 1999-2009, together with their parents. We applied multivariable regression, classic Mendelian randomization (classic MR), and within-family Mendelian randomization (within-family MR). We report estimates of the effects of the child's own BMI, mother's BMI, and father's BMI on the child's depressive, anxiety, and ADHD symptoms, reported by mothers when the child was aged 8. Results: In multivariable regression, higher BMI was marginally associated with more depressive and ADHD symptoms, and associated with fewer anxiety symptoms, in 8-year-old children. Classic MR models implied a causal effect of children's higher BMI on higher depressive and ADHD symptoms, and to a lesser degree, lower anxiety symptoms. In within-family MR models, there was less evidence that children's own BMI affected any of these symptoms. For example, a 5kg/m2 increase in BMI was associated with 0.04 standard deviations (SD) higher depressive symptoms (95% CI -0.01 to 0.09) in multivariable regression, with corresponding effect estimates of 0.41 SD (95% CI 0.10 to 0.56) in classic MR and 0.08 SD (95% CI -0.25 to 0.42) in within-family MR. Within-family MR suggested that maternal but not paternal BMI was associated with children's depressive symptoms. Conclusions: The influence of childhood BMI on depressive, anxiety and ADHD symptoms may have been overstated by MR approaches that do not account for parental genotype. Factors correlated with maternal BMI may influence offspring symptoms of depression.