Pharmacopsychiatry 2019; 52(01): 16-23
DOI: 10.1055/s-0043-125392
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Fat Mass and Obesity-Related Gene Variants rs9939609 and rs7185735 are Associated with Second-Generation Antipsychotic-Induced Weight Gain

Charlotte Schröder
1   Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technischen Universität München, München, Germany
,
Fabian Czerwensky
1   Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technischen Universität München, München, Germany
,
Stefan Leucht
2   Klinik für Psychiatrie und Psychotherapie, Klinikum rechts der Isar, Technischen Universität München, München, Germany
,
Werner Steimer
1   Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technischen Universität München, München, Germany
› Author Affiliations
Further Information

Publication History

received 28 June 2017
revised 12 December 2017

accepted 19 December 2017

Publication Date:
15 January 2018 (online)

Abstract

Introduction Weight gain is a limiting and frequent adverse effect of second-generation antipsychotic therapy. Identifying genetic risk factors would significantly improve pharmacotherapy.

Methods We focused on rs7185735 and rs9939609, 2 common single nucleotide polymorphisms of the fat mass and obesity-associated (FTO) gene reported to be associated with obesity. Three-hundred fifty Caucasian inpatients were included in a naturalistic study.

Results After 4 weeks of treatment, we did not observe any significant association of polymorphisms with weight change in the whole study population (p>0.05). In a subpopulation without additional weight-inducing comedication (n=178), G-allele carriers of rs7185735 gained 3.4 times more weight (1.69 kg±3.1 kg, p=0.019) than AA genotypes (0.49 kg±3.1 kg). A-allele carriers of rs9939609 gained 3.1 times more weight (1.65 kg±3.1 kg, p=0.029) than TT genotypes (0.54 kg±3.2 kg).

Discussion Our findings confirm the role of the FTO gene as a high-potential risk factor for obesity and indicate a value for predicting a weight gain induced by second-generation antipsychotics. Further, we detected an additive effect of FTO rs7185735 and MC4R rs17782313.

Supporting Information

 
  • References

  • 1 Leucht S, Cipriani A, Spineli L. et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 2013; 382: 951-962
  • 2 Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res. 2004; 66: 51-57
  • 3 Shams TA, Muller DJ. Antipsychotic induced weight gain: Genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep. 2014; 16: 473
  • 4 Goncalves VF, Zai CC, Tiwari AK. et al. A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2014; 39: 1347-1354
  • 5 Shen J, Ge W, Zhang J. et al. Leptin -2548 g/a gene polymorphism in association with antipsychotic-induced weight gain: A meta-analysis study. Psychiat Danub 2014; 26: 145-151
  • 6 De Luca V, Mueller DJ, de Bartolomeis A. et al. Association of the HTR2C gene and antipsychotic induced weight gain: A meta-analysis. Int J Neuropsychopharmacol. 2007; 10: 697-704
  • 7 Czerwensky F, Leucht S, Steimer W. Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain. J Clin Psychopharmacol. 2013; 33: 74-79
  • 8 Stratigopoulos G, Padilla SL, LeDuc CA. et al. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 2008; 294: R1185-R1196
  • 9 Berulava T, Ziehe M, Klein-Hitpass L. et al. FTO levels affect RNA modification and the transcriptome. Eur J Hum Genet 2013; 21: 317-323
  • 10 Church C, Moir L, McMurray F. et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010; 42: 1086-1092
  • 11 Fischer J, Koch L, Emmerling C. et al. Inactivation of the Fto gene protects from obesity. Nature 2009; 458: 894-898
  • 12 Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends Genet. 2010; 26: 266-274
  • 13 Tan LJ, Zhu H, He H. et al. Replication of 6 obesity genes in a meta-analysis of genome-wide association studies from diverse ancestries. PLoS One 2014; 9: e96149
  • 14 Quan LL, Wang H, Tian Y. et al. Association of fat-mass and obesity-associated gene FTO rs9939609 polymorphism with the risk of obesity among children and adolescents: A meta-analysis. Eur Rev Med Pharmacol Sci. 2015; 19: 614-623
  • 15 Xi B, Cheng H, Shen Y. et al. Study of 11 BMI-associated loci identified in GWAS for associations with central obesity in the Chinese children. PLoS One 2013; 8: e56472
  • 16 Frayling TM, Timpson NJ, Weedon MN. 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: 889-894
  • 17 Scuteri A, Sanna S, Chen WM. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007; 3: e115
  • 18 Song X, Pang L, Feng Y. et al. Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia. Behav Brain Funct. 2014; 10: 35
  • 19 Shing EC, Tiwari AK, Brandl EJ. et al. Fat mass- and obesity-associated (FTO) gene and antipsychotic-induced weight gain: An association study. Neuropsychobiology 2014; 69: 59-63
  • 20 Reynolds GP, Yevtushenko OO, Gordon S. et al. The obesity risk gene FTO influences body mass in chronic schizophrenia but not initial antipsychotic drug-induced weight gain in first-episode patients. Int J Neuropsychopharmacol. 2013; 16: 1421-1425
  • 21 Perez-Iglesias R, Mata I, Amado JA. et al. Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. J Clin Psychopharmacol. 2010; 30: 661-666
  • 22 Jassim G, Fernø J, Theisen FM. et al. Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry 2011; 44: 15-20
  • 23 Popp J, Messner B, Steimer W. High-speed genotyping of CYP1A2*1 F mutation with fluorescent hybridization probes using the LightCycler. Pharmacogenomics 2003; 4: 643-646
  • 24 Sharma E, Rao NP, Venkatasubramanian G. Association between antipsychotic-induced metabolic side-effects and clinical improvement: A review on the Evidence for “metabolic threshold”. Asian J Psychiatr 2014; 8: 12-21
  • 25 Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M. et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res. 2009; 43: 620-626
  • 26 Reas DL, Nygard JF, Svensson E. et al. Changes in body mass index by age, gender, and socio-economic status among a cohort of Norwegian men and women (1990–2001). BMC Public Health 2007; 7: 269
  • 27 Jackson AS, Stanforth PR, Gagnon J. et al. The effect of sex, age and race on estimating percentage body fat from body mass index: The Heritage Family Study. Int J Obes Relat Metab Disord 2002; 26: 789-796
  • 28 Kloiber S, Domschke K, Ising M. et al. Clinical risk factors for weight gain during psychopharmacologic treatment of depression: Results from 2 large German observational studies. J Clin Psychiatry. 2015; 76: E802-E808
  • 29 Huang W, Sun Y, Sun J. Combined effects of FTO rs9939609 and MC4R rs17782313 on obesity and BMI in Chinese Han populations. Endocrine 2011; 39: 69-74
  • 30 Cauchi S, Stutzmann F, Cavalcanti-Proença C. et al. Combined effects of MC4R and FTO common genetic variants on obesity in European general populations. J Mol Med. 2009; 87: 537-546
  • 31 Church C, Lee S, Bagg EAL. et al. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet. 2009; 5: e1000599
  • 32 Gulati P, Yeo GSH. The biology of FTO: From nucleic acid demethylase to amino acid sensor. Diabetologia 2013; 56: 2113-2121
  • 33 Landgraf K, Scholz M, Kovacs P. et al. FTO obesity risk variants are linked to adipocyte IRX3 expression and BMI of children – relevance of FTO variants to defend body weight in lean children?. PLoS One 2016; 11: e0161739
  • 34 Smemo S, Tena JJ, Kim KH. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 2014; 507: 371-375
  • 35 Kinon BJ, Kaiser CJ, Ahmed S. et al. Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders. J Clin Psychopharmacol. 2005; 25: 255-258
  • 36 Vandenberghe F, Gholam-Rezaee M, Saigi-Morgui N. et al. Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015; 76: e1417-e1423