Higher adiposity and mental health: causal inference using Mendelian randomization

Abstract

Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one- and two- sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß: -0.15, 95%CI: -0.26, -0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being.

Figure 1

Two-sample Mendelian randomization IVW results for BMI, favourable and unfavourable adiposity in UK Biobank representing (A) odds of the binary mental health outcome per standard deviation change in genetically determined BMI, 95% confidence interval in brackets and (B) betas representing standard deviation change in the continuous mental health outcome per standard deviation change in genetically determined BMI, 95% confidence interval in brackets.

Figure 2

Summary of the results from the non-linear Mendelian randomization for (A) PHQ9 severity, (B) current GAD and (C) well-being score. Betas (continuous) and odds ratios (binary) represent the difference in mental health outcome per unit higher BMI. Results are presented for all individuals and male and females separately.