Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study
Chi-Fa Hung, Margarita Rivera, Nick Craddock, Michael J. Owen, Michael Gill, Ania Korszun, Wolfgang Maier, Ole Mors, Martin Preisig, John P. Rice, Marcella Rietschel, Lisa Jones, Lefkos Middleton, Kathy J. Aitchison, Oliver S. P. Davis, Gerome Breen, Cathryn Lewis, Anne Farmer, Peter McGuffin
  • Declaration of interest

    A.F. and P.M. have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including GlaxoSmithKline. P.M. has received speaker’s fees from Pfizer. K.J.A. has been on the advisory board for Bristol-Myers Squibb and Otsuka Pharmaceuticals Ltd, and received consultancy fees including payment for lectures and educational presentations from the same company. She was previously a member of other advisory boards, receiving consultancy fees and honoraria, and has received research grants from various companies including Lundbeck and GlaxoSmithKline. M.J.O. has recently received an honorarium from Janssen. W.M. is member of the advisory boards/has received fees for speaking from Lilly and Lundbeck. M.P. is part of advisory boards for Eli Lilly and Lundbeck. L.M. has received consultancy fees from Johnson & Johnson.



Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMI) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue.


To investigate whether higher BMI increases the risk of major depression.


Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMI.


Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMI. Probit regression suggested that higher BMI is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMI and major depression (FTO genotype: coefficient –0.03, 95% CI –0.18 to 0.13, P = 0.73; GRS: coefficient –0.02, 95% CI –0.11 to 0.07, P = 0.62).


Our instrumental variable analyses did not support a causal relationship between higher BMI and major depression. The positive associations of higher BMI with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding.


  • Funding

    This study was funded by the UK Medical Research Council and GlaxoSmithKline (G0701420). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair funded by the Government of Alberta. O.S.P.D. was supported by a Sir Henry Wellcome Fellowship from the Wellcome Trust (WT088984). This work was funded in part by the National Institute for Health Research (NIHR)Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King’s College London. This article/paper/report presents independent research in part funded by the NIHR. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health.

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