Skip to main content Accessibility help
×
Home

Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study

  • Chi-Fa Hung (a1), Margarita Rivera (a2), Nick Craddock (a3), Michael J. Owen (a3), Michael Gill (a4), Ania Korszun (a5), Wolfgang Maier (a6), Ole Mors (a7), Martin Preisig (a8), John P. Rice (a9), Marcella Rietschel (a10), Lisa Jones (a11), Lefkos Middleton (a12), Kathy J. Aitchison (a13), Oliver S. P. Davis (a14), Gerome Breen (a15), Cathryn Lewis (a16), Anne Farmer (a15) and Peter McGuffin (a15)...

Abstract

Background

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.

Aims

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

Method

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.

Results

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).

Conclusions

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.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study
      Available formats
      ×

Copyright

Corresponding author

Margarita Rivera, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, UK. Email: margarita.rivera_sanchez@kcl.ac.uk

Footnotes

Hide All

These authors contributed equally to the work.

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.

Footnotes

References

Hide All
1 Flegal, KM, Carroll, MD, Ogden, CL, Curtin, LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA 2010; 303: 235–41.
2 Wang, YC, McPherson, K, Marsh, T, Gortmaker, SL, Brown, M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 2011; 378: 815–25.
3 Farmer, A, Korszun, A, Owen, MJ, Craddock, N, Jones, L, Jones, I, et al. Medical disorders in people with recurrent depression. Br J Psychiatry 2008; 192: 351–5.
4 Zhang, C, Rexrode, KM, van Dam, RM, Li, TY, Hu, FB. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality. Circulation 2008; 117: 1658–67.
5 de Wit, L, Luppino, F, van Straten, A, Penninx, B, Zitman, F, Cuijpers, P. Depression and obesity: a meta-analysis of community-based studies. Psychiatry Res 2010; 178: 230–5.
6 Luppino, FS, de Wit, LM, Bouvy, PF, Stijnen, T, Cuijpers, P, Penninx, BWJH, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010; 67: 220.
7 Anderson, SE, Cohen, P, Naumova, EN, Jacques, PF, Must, A. Adolescent obesity and risk for subsequent major depressive disorder and anxiety disorder: prospective evidence. Psychosom Med 2007; 69: 740–7.
8 Roberts, RE, Deleger, S, Strawbridge, WJ, Kaplan, GA. Prospective association between obesity and depression: evidence from the Alameda County Study. Int J Obes 2003; 27: 514–21.
9 Hickie, I, Scott, E, Naismith, S, Ward, P, Turner, K, Parker, G, et al. Late-onset depression: genetic, vascular and clinical contributions. Psychol Med 2001; 31: 1403–12.
10 Beydoun, MA, Wang, Y. Pathways linking socioeconomic status to obesity through depression and lifestyle factors among young US adults. J Affect Disord 2010; 123: 5263.
11 Sheehan, NA, Didelez, V, Burton, PR, Tobin, MD. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med 2008; 5: e177.
12 Jokela, M, Elovainio, M, Keltikangas-Jarvinen, L, Batty, GD, Hintsanen, M, Seppala, I, et al. Body mass index and depressive symptoms: instrumental-variables regression with genetic risk score. Genes Brain Behav 2012; Sep 7 (Epub ahead of print).
13 Kivimaki, M, Jokela, M, Hamer, M, Geddes, J, Ebmeier, K, Kumari, M, et al. Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: the Whitehall II Study, 1985-2004. Am J Epidemiol 2011; 173: 421–9.
14 Lawlor, DA, Harbord, RM, Tybjaerg-Hansen, A, Palmer, TM, Zacho, J, Benn, M, et al. Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. J Intern Med 2011; 269: 525–37.
15 Speliotes, EK, Willer, CJ, Berndt, SI, Monda, KL, Thorleifsson, G, Jackson, AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–48.
16 Palmer, TM, Lawlor, DA, Harbord, RM, Sheehan, NA, Tobias, JH, Timpson, NJ, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 2012; 21: 223–42.
17 Farmer, A, Breen, G, Brewster, S, Craddock, N, Gill, M, Korszun, A, et al. The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study. BMC Psychiatry 2004; 4: 42.
18 Cohen-Woods, S, Gaysina, D, Craddock, N, Farmer, A, Gray, J, Gunasinghe, C, et al. Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder. Hum Mol Genet 2009; 18: 1504–9.
19 Uher, R, Huezo-Diaz, P, Perroud, N, Smith, R, Rietschel, M, Mors, O, et al. Genetic predictors of response to antidepressants in the GENDEP project. Pharmacogenomics J 2009; 9: 225–33.
20 Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, J, Giel, R, et al. SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990; 47: 589.
21 McGuffin, P, Katz, R, Aldrich, J. Past and present state examination: the assessment of ‘lifetime ever'psychopathology. Psychol Med 1986; 16: 461–5.
22 Lewis, CM, Ng, MY, Butler, AW, Cohen-Woods, S, Uher, R, Pirlo, K, et al. Genome-wide association study of major recurrent depression in the UK population. Am J Psychiatry 2010; 167: 949–57.
23 Price, AL, Patterson, NJ, Plenge, RM, Weinblatt, ME, Shadick, NA, Reich, D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–9.
24 Glymour, MM, Tchetgen, EJ, Robins, JM. Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. Am J Epidemiol 2012; 175: 332–9.
25 Goldberg, DP. The Detection of Psychiatric Illness by Questionnaire: A Technique for the Identification and Assessment of Non-Psychotic Psychiatric Illness. Oxford University Press, 1972.
26 Chaiton, M, Cohen, J, O'Loughlin, J, Rehm, J. A systematic review of longitudinal studies on the association between depression and smoking in adolescents. BMC Public Health 2009; 9: 356.
27 Beck, AT, Steer, RA, Brown, GK. Manual for the Beck Depression Inventory-II. Psychological Corporation, 1996.
28 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). APA, 1994.
29 Wray, N, Pergadia, M, Blackwood, D, Penninx, B, Gordon, S, Nyholt, D, et al. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry 2012; 17: 3648.
30 Serretti, A, Mandelli, L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry 2010; 71: 1259–72.
31 Puhl, RM, Heuer, CA. Obesity stigma: important considerations for public health. Am J Public Health 2010; 100: 1019–28.
32 Penninx, BWJH, Milaneschi, Y, Lamer, F, Vogelzangs, N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med 2013; 11: 129.
33 Srinivasan, SR, Bao, W, Wattigney, WA, Berenson, GS. Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 1996; 45: 235.
34 Guo, S, Huang, C, Maynard, LM, Demerath, E, Towne, B, Chumlea, WC, et al. Body mass index during childhood, adolescence and young adulthood in relation to adult overweight and adiposity: the Fels Longitudinal Study. Int J Obes Relat Metab Disord 2000; 24: 1628.
35 Mumby, HS, Elks, CE, Li, S, Sharp, SJ, Khaw, K-T, Luben, RN, et al. Mendelian randomisation study of childhood BMI and early menarche. J Obes 2011; 2011: 180729.
36 Pierce, BL, Ahsan, H, VanderWeele, TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 2011; 40: 740–52.
Type Description Title
PDF
Supplementary materials

Hung et al. supplementary material
Supplementary Table S1

 PDF (32 KB)
32 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Relationship between obesity and the risk of clinically significant depression: Mendelian randomisation study

  • Chi-Fa Hung (a1), Margarita Rivera (a2), Nick Craddock (a3), Michael J. Owen (a3), Michael Gill (a4), Ania Korszun (a5), Wolfgang Maier (a6), Ole Mors (a7), Martin Preisig (a8), John P. Rice (a9), Marcella Rietschel (a10), Lisa Jones (a11), Lefkos Middleton (a12), Kathy J. Aitchison (a13), Oliver S. P. Davis (a14), Gerome Breen (a15), Cathryn Lewis (a16), Anne Farmer (a15) and Peter McGuffin (a15)...
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *