Obesity as a causal risk factor for depression: Systematic review and meta-analysis of Mendelian Randomization studies and implications for population mental health

Background/objectives: Obesity has been associated with elevated risk of depression. If this association is causal, the increasing obesity prevalence might lead to worsening population mental health, but the strength of the causal effect has not been systematically evaluated. Subjects/methods: The current study provides a systematic review and meta-analysis of studies examining associations between body mass index and depression using Mendelian randomization with multiple genetic variants as instruments for body mass index. We used this estimate to calculate the expected changes in prevalence of population psychological distress from the 1990s-2010s, which were compared with the empirically observed trends in psychological distress in the Health Survey for England (HSE) and U.S. National Health Interview Surveys (NHIS).Results: Meta-analysis of 8 Mendelian randomization studies indicated an OR = 1.33 higher depression risk associated with obesity (95% confidence interval 1.19, 1.48). Between 15% and 20% of the participants of HSE and NHIS reported at least moderate psychological distress. The increase of obesity prevalence from the 1990s-2010s in HSE and NHIS would have led to a 0.6 percentage-point increase in population psychological distress. Conclusions: Mendelian randomization studies suggest that obesity is a causal risk factor for elevated risk of depression. The increasing obesity rates may have modestly increased the prevalence of depressive symptoms in the general population. Mendelian randomization relies on methodological assumptions that may not always hold, so other quasi-experimental methods are needed to confirm the current conclusions.