Higher adiposity and mental health: causal inference using Mendelian randomization

Francesco Casanova, Jessica O’Loughlin, Robin N Beaumont, Andrew R Wood, Edward R Watkins, Rachel M Freathy, Saskia P Hagenaars, Timothy M Frayling, Hanieh Yaghootkar, Jess Tyrrell

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21 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2371-2382
Number of pages12
JournalHuman Molecular Genetics
Issue number24
Early online date16 Jul 2021
Publication statusPublished - 15 Dec 2021


  • Genetics(clinical)
  • Genetics
  • Molecular Biology
  • General Medicine


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