Association Study of 60 Candidate Genes with Antipsychotic-induced Weight Gain in Schizophrenia Patients

Abstract

Introduction: This study aimed to investigate the association of multiple candidate genes with weight gain and appetite change during antipsychotic treatment.

Methods: A total of 233 single nucleotide polymorphisms (SNPs) within 60 candidate genes were genotyped. BMI changes for up to 8 weeks in 84 schizophrenia patients receiving antipsychotic medication were analyzed using a linear mixed model. In addition, we assessed appetite change during antipsychotic treatment in a different group of 46 schizophrenia patients using the Drug-Related Eating Behavior Questionnaire.

Results: No SNP showed a statistically significant association with BMI or appetite change after correction for multiple testing. We observed trends of association (P<0.05) between 19 SNPs of 11 genes and weight gain, and between 7 SNPs of 5 genes and appetite change. In particular, rs696217 in GHRL showed suggestive evidence of association with not only weight gain (P=0.001) but also appetite change (P=0.042). Patients carrying the GG genotype of rs696217 exhibited higher increase in both BMI and appetite compared to patients carrying the GT/TT genotype.

Discussion: Our findings suggested the involvement of a GHRL polymorphism in weight gain, which was specifically mediated by appetite change, during antipsychotic treatment in schizophrenia patients.

Key words

pharmacogenetics - schizophrenia - antipsychotic-induced weight gain - appetite - GHRL

• References

• 1 Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 2007; 68 (Suppl. 01) 20-27
• 2 Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004; 65 (Suppl. 18) 13-26
• 3 Basile VS, Masellis M, McIntyre RS et al. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry 2001; 62 (Suppl. 23) 45-66
• 4 Muller DJ, Kennedy JL. Genetics of antipsychotic treatment emergent weight gain in schizophrenia. Pharmacogenomics 2006; 7: 863-887
• 5 Lett TA, Wallace TJ, Chowdhury NI et al. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 2012; 17: 242-266
• 6 Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359: 2086-2087
• 7 Zhang XY, Tan YL, Zhou DF et al. Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population. J Clin Psychopharmacol 2007; 27: 246-251
• 8 Malhotra AK, Correll CU, Chowdhury NI et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 2012; 69: 904-912
• 9 Ujike H, Nomura A, Morita Y et al. Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J Clin Psychiatry 2008; 69: 1416-1422
• 10 McIntyre RS, Mancini DA, Basile VS. Mechanisms of antipsychotic-induced weight gain. J Clin Psychiatry 2001; 62 (Suppl. 23) 23-29
• 11 Baptista T, ElFakih Y, Uzcategui E et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 2008; 22: 477-495
• 12 Ryu S, Nam HJ, Oh S et al. Eating-behavior changes associated with antipsychotic medications in patients with schizophrenia as measured by the drug-related eating behavior questionnaire. J Clin Psychopharmacol 2013; 33: 120-122
• 13 Miller DD, Ellingrod VL, Holman TL et al. Clozapine-induced weight gain associated with the 5HT2C receptor − 759C/T polymorphism. Am J Med Genet B Neuropsychiatr Genet 2005; 133B: 97-100
• 14 Ryu S, Cho EY, Park T et al. − 759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 673-677
• 15 Cowley MA, Smith RG, Diano S et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649-661
• 16 Date Y, Kojima M, Hosoda H et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 4255-4261
• 17 Esen-Danaci A, Sarandol A, Taneli F et al. Effects of second generation antipsychotics on leptin and ghrelin. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1434-1438
• 18 Zhang Q, Deng C, Huang XF. The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology 2013; 38: 2423-2438
• 19 Ukkola O, Ravussin E, Jacobson P et al. Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. J Clin Endocrinol Metab 2001; 86: 3996-3999
• 20 Korbonits M, Gueorguiev M, O’Grady E et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J Clin Endocrinol Metab 2002; 87: 4005-4008
• 21 Miraglia del Giudice E, Santoro N, Cirillo G et al. Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Relat Metab Disord 2004; 28: 447-450
• 22 Ukkola O, Ravussin E, Jacobson P et al. Role of ghrelin polymorphisms in obesity based on three different studies. Obes Res 2002; 10: 782-791
• 23 Liao N, Xie ZK, Huang J et al. Association between the ghrelin Leu72Met polymorphism and type 2 diabetes risk: a meta-analysis. Gene 2013; 517: 179-183
• 24 Leskela P, Ukkola O, Vartiainen J et al. Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity. Metabolism 2009; 58: 174-179
• 25 Sickert L, Muller DJ, Tiwari AK et al. Association of the alpha 2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European-Americans. Pharmacogenomics 2009; 10: 1169-1176
• 26 Roffeei SN, Reynolds GP, Zainal NZ et al. Association of ADRA2A and MTHFR gene polymorphisms with weight loss following antipsychotic switching to aripiprazole or ziprasidone. Hum Psychopharmacol 2014; 29: 38-45
• 27 Wang YC, Bai YM, Chen JY et al. Polymorphism of the adrenergic receptor alpha 2a -1291C>G genetic variation and clozapine-induced weight gain. J Neural Transm 2005; 112: 1463-1468
• 28 Park YM, Chung YC, Lee SH et al. Weight gain associated with the alpha2a-adrenergic receptor -1,291 C/G polymorphism and olanzapine treatment. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 394-397
• 29 Lane HY, Liu YC, Huang CL et al. Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006; 26: 128-134
• 30 Lencz T, Robinson DG, Napolitano B et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics 2010; 20: 569-572
• 31 Muller DJ, Zai CC, Sicard M et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J 2012; 12: 156-164
• 32 Popp J, Leucht S, Heres S et al. DRD4 48 bp VNTR but not 5-HT 2C Cys23Ser receptor polymorphism is related to antipsychotic-induced weight gain. Pharmacogenomics J 2009; 9: 71-77