Revisiting mendelian randomization studies of the effect of body mass index on depression

Mendelian Randomization studies, which use genetic instrumental variables (IVs) as quasi-experiments to estimate causal effects, report inconsistent findings regarding effects of body mass index (BMI) on mental health. We used genetic IV to estimate effects of BMI on depression and evaluated validity of a commonly used IV. Female Nurse's Health Study participants (n=6989, average age 56.4, [Standard Deviation 6.91] years at first depression assessment) self-reported BMI, which was averaged across eight reports prior to depression assessment (mean=24.96, SD 4.50). Genetic instruments included fat mass and obesity-associated protein (FTO) alleles, melanocortin receptor 4 (MC4R) alleles, and polygenic risk scores based on 32 established polymorphisms for BMI. Depression was assessed using multiple symptom measures, scaled to the Geriatric Depression Scale 15, averaged across up to 7 biennial waves. We used over-identification tests to assess the validity of genetic IVs. In conventional estimates, each additional BMI point predicted 0.024 (95% Confidence Interval (CI): 0.020-0.029) higher average depression scores. Genetic IV estimates were not significant when based on FTO (beta: 0.064, CI: -0.014, 0.142), MC4R (beta: 0.005, CI: -0.146, 0.156), polygenic score excluding FTO (beta=-0.003, 95%-CI -0.051, 0.045), or mechanism-specific scores. The over-identification test comparing IV estimates based on FTO to estimates based on the polygenic score excluding FTO rejected equality of estimated effects (P=0.014). Results provide no evidence against a null effect of BMI on depression and call into question validity of FTO as an instrument for BMI in Mendelian Randomization studies.