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Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals

  • Margarita Rivera (a1), Adam E. Locke (a2), Tanguy Corre (a3), Darina Czamara (a4), Christiane Wolf (a4), Ana Ching-Lopez (a5), Yuri Milaneschi (a6), Stefan Kloiber (a4), Sara Cohen-Woods (a7), James Rucker (a8), Katherine J. Aitchison (a9), Sven Bergmann (a3), Dorret I. Boomsma (a10), Nick Craddock (a11), Michael Gill (a12), Florian Holsboer (a4), Jouke-Jan Hottenga (a9), Ania Korszun (a13), Zoltan Kutalik (a3), Susanne Lucae (a4), Wolfgang Maier (a14), Ole Mors (a15), Bertram Müller-Myhsok (a4), Michael J. Owen (a16), Brenda W. J. H. Penninx (a6), Martin Preisig (a17), John Rice (a18), Marcella Rietschel (a19), Federica Tozzi (a20), Rudolf Uher (a21), Peter Vollenweider (a22), Gerard Waeber (a22), Gonneke Willemsen (a9), Ian W. Craig (a8), Anne E. Farmer (a8), Cathryn M. Lewis (a23), Gerome Breen (a8) and Peter McGuffin (a8)...
Abstract
Background

Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.

Aims

To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.

Method

The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.

Results

In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.

Conclusions

This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.

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Copyright
Corresponding author
Margarita Rivera, PhD, Center for Biomedical Research, University of Granada, Avda. del Conocimiento, s/n, Armilla, Granada 18016, Spain. Email: margarita.rivera_sanchez@kcl.ac.uk
Footnotes
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See editorial, pp. 61–62, this issue.

Declaration of interest

K.J.A., A.E.F. and P.M. have received consultancy fees and honoraria for participating in expert panels for pharmaceutical companies including GlaxoSmithKline (GSK). P.M. has received speaker's fees from Pfizer. K.J.A. has been on the advisory board for Bristol-Myers Squibb and Otsuka Pharmaceutical and in addition received consultancy fees including payment for lectures and educational presentations. 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 GSK. F.H. is co-founder of the biotech company Holsboer Maschmeyer Neuro Chemie GmbH (HMNC GmbH) in Germany. W.M. is a member of the advisory boards and has received fees for speaking from Lilly and Lundbeck. M.P. is part of advisory boards for Eli Lilly and Lundbeck.

Footnotes
References
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1 Mathers, CD, Loncar, D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3: e442.
2 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.
3 Afari, N, Noonan, C, Goldberg, J, Roy-Byrne, P, Schur, E, Golnari, G, et al. Depression and obesity: do shared genes explain the relationship? Depress Anxiety 2010; 27: 799806.
4 Luppino, FS, de Wit, LM, Bouvy, PF, Stijnen, T, Cuijpers, P, Penninx, BW, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010; 67: 220–9.
5 Loos, RJ, Bouchard, C. FTO: the first gene contributing to common forms of human obesity. Obes Rev 2008; 9: 246–50.
6 Frayling, TM, Timpson, NJ, Weedon, MN, Zeqqini, E, Frealthy, RM, Lindgren, CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–94.
7 Dina, C, Meyre, D, Gallina, S, Durand, E, Körner, A, Jacobson, P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–6.
8 Cotsapas, C, Speliotes, EK, Hatoum, IJ, Greenawalt, DM, Dobrin, T, Lum, PY, et al. Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet 2009; 18: 3502–7.
9 Hinney, A, Nguyen, TT, Scherag, A, Friedel, S, Brönner, G, Müller, TD, et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLOS ONE 2007; 2: e1361.
10 Fawcett, KA, Barroso, I. The genetics of obesity: FTO leads the way. Trends Genet 2010; 26: 266–74.
11 Scuteri, A, Sanna, S, Chen, WM, Uda, M, Albai, G, Strait, J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3: e115.
12 Speliotes, EK, Wilier, CJ, Berndt, SI, Monda, KL, Thorleifsson, G, Jackson, ALL, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–48.
13 Thorleifsson, G, Walters, GB, Gudbjartsson, DF, Steinthorsdottir, V, Sulem, P, Helgadottir, A, et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 1824.
14 Gerken, T, Girard, CA, Tung, YC, Webby, CJ, Saudek, V, Hewitson, KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007; 318: 1469–72.
15 Cecil, JE, Tavendale, R, Watt, P, Hetherington, MM, Palmer, CN. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008; 359: 2558–66.
16 Wardle, J, Carnell, S, Haworth, CM, Farooqi, IS, O'Rahilly, S, Plomin, R. Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab 2008; 93: 3640–3.
17 Cole, JH, Boyle, CP, Simmons, A, Cohen-Woods, S, Rivera, M, McGuffin, P, et al. Body mass index, but not FTO genotype or major depressive disorder, influences brain structure. Neuroscience 2013; 252: 109–17.
18 Ho, AJ, Stein, JL, Hua, X, Lee, S, Hibar, DP, Leow, AD, et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci 2010; 107: 8404–9.
19 Rivera, M, Cohen-Woods, S, Kapur, K, Breen, G, Ng, MY, Butler, AW, et al. Depressive disorder moderates the effect of the FTO gene on body mass index. Mol Psychiatry 2012; 17: 604–11.
20 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.
21 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.
22 McGuffin, P, Knight, J, Breen, G, Brewster, S, Boyd, PR, Craddock, N, et al. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum Mol Genet 2005; 14: 3337–45.
23 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.
24 Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, et al. SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990; 47: 589–93.
25 McGuffin, P, Katz, R, Aldrich, J. Past and present state examination: the assessment of ‘lifetime ever’ psychopathology. Psychol Med 1986; 16: 461–5.
26 Firmann, M, Mayor, V, Vidal, PM, Bochud, M, Pécoud, A, Hayoz, D, et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc Disord 2008; 8: 6.
27 Preisig, M, Waeber, G, Vollenweider, P, Bovet, P, Rothen, S, Vandeleur, C, et al. The PsyCoLaus study: methodology and characteristics of the sample of a population-based survey on psychiatric disorders and their association with genetic and cardiovascular risk factors. BMC Psychiatry 2009; 9: 9.
28 Nurnberger, JI Jr, Blehar, MC, Kaufmann, CA, York-Cooler, C, Simpson, SG, Harkavy-Friedman, J, et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994; 51: 849–59.
29 Lucae, S, Salyakina, D, Barden, N, Harvey, M, Gagné, B, Labbé, M, et al. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum Mol Genet 2006; 15: 2438–45.
30 Hennings, JM, Owashi, T, Binder, EB, Horstmann, S, Menke, A, Kloiber, S, et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients – findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 2009; 43: 215–29.
31 Penninx, BW, Beekman, AT, Smit, JH, Zitman, FG, Nolen, WA, Spinhoven, P, et al. The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods, Int J Methods Psychiatr Res 2008; 17: 121–40.
32 Willemsen, G, de Geus, EJ, Bartels, M, van Beijsterveldt, CE, Brooks, AL, Estourgie-van Burk, GF, et al. The Netherlands Twin Register biobank: a resource for genetic epidemiological studies. Twin Res Hum Genet 2010; 13: 231–45.
33 Ter Smitten, MH, Smeets, RMW, Van der Brink, W. Composite International Diagnostic Interview (CIDI), Version 2.1, 12-Months. World Health Organization, 1998.
34 Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatr 2013; 18: 497511.
35 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.
36 Ising, M, Lucae, S, Binder, EB, Bettecken, T, Uhr, M, Ripke, S, et al. A genome-wide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry 2009; 66: 966–75.
37 Nivard, MG, Mbarek, H, Hottenga, JJ, Smit, JH, Jansen, R, Penninx, BW, et al. Further confirmation of the association between anxiety and CTNND2: replication in humans. Genes Brain Behav 2014; 13: 195201.
38 Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–75.
39 Han, B, Eskin, E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Gen 2011; 88: 586–98.
40 Penninx, BW, Milaneschi, Y, Lamers, F, Vogelzangs, N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med 2013; 11: 129.
41 Lamers, F, Vogelzangs, N, Merikangas, KR, de Jonge, P, Beekman, AT, Penninx, BW. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 2013; 18: 692–9.
42 Green, MA, Scott, NA, Cross, SE, Liao, KY, Hallengren, JJ, Davids, CM, et al. Eating disorder behaviors and depression: a minimal relationship beyond social comparison, self-esteem, and body dissatisfaction. J Clin Psychol 2009; 65: 989–99.
43 Friedman, KE, Reichmann, SK, Costanzo, PR, Zelli, A, Ashmore, JA, Musante, GJ. Weight stigmatization and ideological beliefs: relation to psychological functioning in obese adults. Obes Res 2005; 13: 907–16.
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Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals

  • Margarita Rivera (a1), Adam E. Locke (a2), Tanguy Corre (a3), Darina Czamara (a4), Christiane Wolf (a4), Ana Ching-Lopez (a5), Yuri Milaneschi (a6), Stefan Kloiber (a4), Sara Cohen-Woods (a7), James Rucker (a8), Katherine J. Aitchison (a9), Sven Bergmann (a3), Dorret I. Boomsma (a10), Nick Craddock (a11), Michael Gill (a12), Florian Holsboer (a4), Jouke-Jan Hottenga (a9), Ania Korszun (a13), Zoltan Kutalik (a3), Susanne Lucae (a4), Wolfgang Maier (a14), Ole Mors (a15), Bertram Müller-Myhsok (a4), Michael J. Owen (a16), Brenda W. J. H. Penninx (a6), Martin Preisig (a17), John Rice (a18), Marcella Rietschel (a19), Federica Tozzi (a20), Rudolf Uher (a21), Peter Vollenweider (a22), Gerard Waeber (a22), Gonneke Willemsen (a9), Ian W. Craig (a8), Anne E. Farmer (a8), Cathryn M. Lewis (a23), Gerome Breen (a8) and Peter McGuffin (a8)...
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