Objectives: Genetic variation in the fat mass- and obesity-associated gene (FTO) has been associated with obesity in the general population. In this study we have investigated these variants for association with antipsychotic-induced weight gain (AIWG). Methods: A total of 218 patients with chronic schizophrenia or schizoaffective disorder treated mostly with clozapine or olanzapine for up to 14 weeks were included in the study. We analyzed 4 polymorphisms in intron 1 of the FTO gene (rs1421085, rs8050136, rs9939609, rs9930506) for association with AIWG using ANCOVA. Results: No statistically significant associations were observed between the single nucleotide polymorphisms and AIWG. However, patients homozygous for the A-allele of rs9939609 gained numerically higher weight than the other genotypic groups (AA: 5.26 ± 6.7%; TA: 4.66 ± 5.6%; TT: 4.21 ± 5.3%). Conclusion: Our current observations suggest that the FTO gene variants investigated may not play a major role in AIWG.

Keywords:
FTO, Association, Antipsychotics, Weight gain, Pharmacogenetics
1.
Correll CU, Leucht S, Kane JM: Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004;161:414-425.
2.
Wetterling T: Bodyweight gain with atypical antipsychotics: a comparative review. Drug Safety 2001;24:59-74.
3.
Lencz T, Malhotra AK: Pharmacogenetics of antipsychotic-induced side effects. Dialogues Clin Neurosci 2009;11:405-415.
4.
Weiden PJ, Mackell JA, McDonnell DD: Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004;66:51-57.
5.
Lett TA, Wallace TJ, Chowdhury NI, Tiwari AK, Kennedy JL, Müller DJ: Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 2012;17:242-266.
6.
Chowdhury NI, Tiwari AK, Souza RP, Zai CC, Shaikh SA, Chen S, Liu F, Lieberman JA, Meltzer HY, Malhotra AK, Kennedy JL, Müller DJ: Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics J 2013;13:272-279.
7.
Jassim G, Fernø J, Theisen FM, Haberhausen M, Christoforou A, Håvik B, Gebhardt S, Remschmidt H, Mehler-Wex C, Hebebrand J, Lehellard S, Steen VM: Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry 2011;44:15-20.
8.
Perez-Iglesias R, Mata I, Amado JA, Berja A, Garcia-Unzueta MT, Martínez García O, Arranz MJ, Vazquez-Barquero JL, Crespo-Facorro B: Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. J Clin Psychopharmacol 2010;30:661-666.
9.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316:889-894.
10.
Zhou D, Liu H, Zhou M, Wang S, Zhang J, Liao L, He F: Common variant (rs9939609) in the FTO gene is associated with metabolic syndrome. Mol Biol Rep 2012;39:6555-6561.
11.
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orru M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007;3:e115.
12.
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ: The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007;318:1469-1472.
13.
Fredriksson R, Hägglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schiöth HB: The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 2008;149:2062-2071.
14.
Olszewski PK, Fredriksson R, Olszewska AM, Stephansson O, Alsiö J, Radomska KJ, Levine AS, Schiöth HB: Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. BMC Neurosci 2009;10:129.
15.
Rask-Andersen M, Almén MS, Olausen HR, Olszewski PK, Eriksson J, Chavan RA, Levine AS, Fredriksson R, Schiöth HB: Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway. BMC Neurosci 2011;12:117.
16.
Zhang XY, Zhou DF, Wu GY, Cao LY, Tan YL, Haile CN, Li J, Lu L, Kosten TA, Kosten TR: BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 2008;33:2200-2205.
17.
Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K: Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009;41:18-24.
18.
Zai GC, Zai CC, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA, Meltzer HY, Potkin SG, Müller DJ, Kennedy JL: The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2012;39:96-101.
19.
Cauchi S, Stutzmann F, Cavalcanti-Proença C, Durand E, Pouta A, Hartikainen AL, Marre M, Vol S, Tammelin T, Laitinen J, Gonzalez-Izquierdo A, Blakemore AI, Elliott P, Meyre D, Balkau B, Järvelin MR, Froguel P: Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med (Berl) 2009;87:537-546.
20.
Malhotra AK, Correll CU, Chowdhury NI, Müller DJ, Gregersen PK, Lee AT, Tiwari AK, Kane JM, Fleischhacker WW, Kahn RS, Ophoff RA, Meltzer HY, Lencz T, Kennedy JL: Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 2012;69:904-912.
21.
Tiwari HK, Patki A, Lieberman J, Stroup TS, Allison DB, Leibel RL, Chung WK: Association of allelic variation in genes mediating aspects of energy homeostasis with weight gain during administration of antipsychotic drugs (CATIE study). Front Genet 2011;2:56.
22.
Tiwari AK, Zai CC, Likhodi O, Lisker A, Singh D, Souza RP, Batra P, Zaidi SH, Chen S, Liu F, Puls I, Meltzer HY, Lieberman JA, Kennedy JL, Müller DJ: A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2010;35:1315-1324.
23.
Basile VS, Masellis M, de Luca V, Meltzer HY, Kennedy JL: -759C/T genetic variation of 5HT2C receptor and clozapine-induced weight gain. Lancet 2002;360:1790-1791.
24.
de Luca V, Müller DJ, de Bartolomeis A, Kennedy JL: Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol 2007;10:697-704.
25.
Müller DJ, de Luca V, Sicard T, King N, Hwang R, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Meltzer HY, Kennedy JL: Suggestive association between the C825T polymorphism of the G-protein β3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur Neuropsychopharmacol 2005;15:525-531.
26.
Müller DJ, Klempan TA, de Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG, Kennedy JL: The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neurosci Lett 2005;379:81-89.
27.
Lahiri DK, Nurnberger JI Jr: A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991;19:5444.
28.
Dudbridge F: Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003;25:115-121.
29.
Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008;66:87-98.
30.
Gauderman WJ, Morrison JM: Quanto 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies. 2006. http://hydra.usc.edu/gxe.
31.
Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007;39:724-726.
32.
Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-1696.
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