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

• Abstract
• Introduction
• Methods
• Subjects
• Candidate gene and SNP selection
• DNA extraction and genotyping
• Statistical methods
• Results
• Discussion
• References

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.

Introduction

Schizophrenia patients treated with antipsychotic medication often develop clinically significant weight gain. As weight gain correlates with poor treatment adherence, damaged quality of life, and further morbidities, including cardiovascular disease and metabolic syndromes, concerns regarding a patient’s weight gain have increased dramatically in the schizophrenia treatment realm [1] [2]. However, the mechanism and predictors of weight gain remain unclear. Inter-individual differences in susceptibility to antipsychotic treatment-emergent weight gain suggest the contribution of genetic factors [3]. Researchers have proposed that some genetic variations could play a significant role in the susceptibility to weight gain [4].

Within the last decade, pharmacogenetic studies to elucidate the genetic predictors of antipsychotic-induced weight gain (AIWG) have focused on genetic variations related to mechanisms of drug action, energy homeostasis, lipid metabolism, and secondary signaling systems [5]. The rs3813929 (−759C/T) of HTR2C [6] and rs7799039 (−2548 G/A) of LEP [7] are the most consistently reported polymorphisms showing an association with AIWG in candidate gene studies. A recent genome-wide association study (GWAS) identified association between SNPs near MC4R and severe AIWG [8]. However, similar to other complex phenotypes, it is likely that many more genes with small effect are involved in the susceptibility to AIWG. Moreover, it is not easy to detect an effect in studies focused on a few SNPs in a single gene. Thus, studies that screen multiple candidate genes across various systems involved in body weight regulation are required to identify relevant variations of AIWG. To our knowledge, this trial was performed in one previous study by Ujike et al. [9]. The authors examined 21 SNPs of 17 genes that are known to be involved in appetite and feeding, obesity, and the pharmaceutical effects of antipsychotic drugs, and identified variations of HTR2A, GNB3, HTR2C, and ADRB3 as genetic risk factors for AIWG [9].

Body weight changes are generally induced by 3 major aspects of energy balance: calorie intake, metabolic activity, and energy expenditure, and antipsychotic medications might affect at least one of these steps through various mediating systems [10]. Appetite stimulation is thought to be one key mediating factor or sub-phenotype in AIWG [11]. In our previous study, we reported that changes in appetite and eating behavior were significantly associated with weight gain during the early phase of antipsychotic treatment [12]. In terms of complexity of genetic basis, individual mediating factors or sub-phenotypes might represent simpler genetic underpinning compared to the final outcome, the body weight change. Thus, it is worth adopting appetite and eating-behavior changes during antipsychotic treatment as an intermediate phenotype in investigations targeting genetic susceptibility to AIWG.

In our previous study, we had replicated earlier findings of association between the − 759C/T polymorphism of the X-chromosomal HTR2C and AIWG [6] [13] in Korean schizophrenia patients [14]. Next, we intended to explore other candidate genes that might be involved in the pathogenesis of AIWG. First, the current study aimed to investigate the association between 60 candidate genes across diverse systems and weight gain for up to 8 weeks of antipsychotic treatment in Korean schizophrenia patients. In addition, we assessed the extent of appetite and eating-behavior changes in a different group of schizophrenia patients receiving antipsychotics and intended to test the associations with the same candidate genes. To the best of our knowledge, this is the first pharmacogenetic study investigating both antipsychotic-related weight gain and appetite change.

Methods

Subjects

Subjects for the association analyses of AIWG included 84 Korean patients who met the DSM-IV criteria for schizophrenia. They had been studied in our previous work to determine HTR2C’s association with AIWG [14]. 58 of these patients were drug-naïve, and the remaining patients had been free of antipsychotic medication for at least 3 months prior to study commencement. Exclusion criteria included any comorbid psychiatric disorder including eating disorders, mood disorders, and substance or alcohol abuse, any medical illness that can affect appetite or body weight, and pregnancy. Patients who took mood stabilizers, antidepressants, or other medicines known to affect appetite or body weight during the study period or within the 3-month period preceding the study were also excluded. The antipsychotic drug treatments administered were monotherapy with risperidone (N=53), olanzapine (N=12), amisulpride (N=5), quetiapine (N=4), or typical antipsychotics (N=10) including haloperidol and trifluoperazine. Dosages were adjusted individually according to clinical judgment. Body weights were monitored, and body mass indices (BMI, kg/m²) were calculated at baseline and weekly after treatment start for up to 8 weeks. Additional descriptions on the subjects are shown in [Table 1].

Subjects for the association analyses of appetite and eating-behavior change during antipsychotic treatment included 46 patients with DSM-IV schizophrenia who had been receiving risperidone (N=27) or olanzapine (N=19) monotherapy for more than 4 weeks, but less than 48 weeks. They were clinically stable at the time of assessment, and could provide reliable information regarding their appetite and eating behavior. The antipsychotic-related change in appetite and eating behavior was measured using the Drug-Related Eating Behavior Questionnaire (DR-EBQ), a questionnaire developed by the authors [12]. DR-EBQ covers various aspects of appetite and eating-behavior changes that occur after a patient begins taking specific medicines, and quantifies the degree of change. The content of each item was presented in a previous paper by Ryu et al. [12]. The demographic and clinical characteristics of these subjects are also summarized in [Table 1].

All patients were recruited from the schizophrenia clinic of the Samsung Medical Center and Asan Medical Center. This study was approved by the institutional review board of each center, and written informed consent was obtained from all subjects.

Candidate gene and SNP selection

Candidate genes known or expected to be related to obesity, metabolic syndrome, feeding behavior, BMI or AIWG, were selected (N=60) from the website database or via literature reviews. When selecting SNPs within the candidate genes, we first selected previously studied SNPs. In addition, for small-sized genes (<approximately 100 kb, N=25), tag SNPs selected by pairwise tagging (minor allele frequencies (MAF)>0.05 or > 0.1 and r²>0.8) were also included. For larger genes (N=35), additional SNPs were selected considering MAF and inter-marker distances. Overall, a total of 233 SNPs in 60 autosomal genes were selected ([Table 2]).

DNA extraction and genotyping

Whole blood specimens were collected from each individual in EDTA tubes, and genomic DNA was isolated from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit according to the manufacturer’s instructions (Promega, Madison, WI, USA). Multiplex SNP genotyping was performed using Sequenom^® MassARRAY iPLEX assay (Sequenom Inc, San Diego, CA, USA). SNP assays were designed using Sequenom’s MassARRAY Assay Design v3.0 Software (primer information is available upon request). PCR was performed according to the standard iPLEX methodology. Spectra were analyzed using MassARRAY Typer v3.4 Software (Sequenom). Quality control was performed by excluding SNPs with MAF<1%, missing data rate>5%, or Hardy-Weinberg equilibrium P<0.05. Finally, we included 211 SNPs of 60 genes in the statistical analysis for AIWG and 181 SNPs of 60 genes for appetite change.

Statistical methods

To investigate the association between genotypes and weight gain over time, BMI changes from baseline across subsequent weeks up to 8 weeks were analyzed using a linear mixed model for repeated measures. In this analysis, sex, age, type of antipsychotics, baseline BMI, time (the time effect on the BMI over this study period), genotypes, and interaction between time and genotypes were used as model covariates, and the ‘unstructured’ covariance structure was applied. Considering the relatively small sample size, the minor homozygote groups of many SNPs would have only a few cases for additive or recessive model, which are not suitable for a linear mixed model analysis. Therefore, we applied only the dominant model in the analyses.

For analyses of association between SNPs and the degree of appetite and eating-behavior change, the mean total scores of the DR-EBQ were compared between those with and without a minor allele using the linear regression analysis controlling for sex, age, baseline BMI, type of antipsychotic drug and duration of medication use.

Adopting Bonferroni correction for multiple testing (number of SNPs tested), associations were designated as statistically significant when P<2.37×10⁻⁴ (0.05/211) for the analysis of AIWG and P<2.76×10⁻⁴ (0.05/181) for appetite change. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc.).

Results

We observed trends of associations between 19 SNPs of 11 genes (NEGR1, SEC16B, ADRA2B, GHRL, DRD1, NTRK2, ADRA2A, DRD2, GRIN2B, HTR2A and COMT) and BMI changes over time (uncorrected P of time×genotype<0.05) ([Table 3]). Negative values for the estimate of the interaction between time and genotypes in [Table 3] indicated that carriers with minor homozygote or heterozygote experienced a lower increase in BMI during antipsychotic treatment, compared to carriers with a major homozygote. In the association analyses for the total scores of the DR-EBQ, we observed association trends with uncorrected P<0.05 in 7 SNPs of 5 genes (POMC, GHRL, GRM3, DRD4 and CHRNA3) ([Table 4]). However, none of these association trends with weight gain and appetite change reached the level of significance after correction for multiple testing. The results of all of the analyzed SNPs are shown in Supplementary Table 1. rs696217 in GHRL, which showed the lowest P-value (uncorrected P=0.001) in the analysis for weight gain ([Table 3]), also revealed a suggestive evidence of association with appetite change (uncorrected P=0.042) ([Table 4]). Patients carrying the GG genotype of rs696217 in GHRL exhibited a higher increase in both BMI an appetite compared to patients carrying the GT/TT genotype.

Discussion

In the current study, we assessed weight gain and appetite change during antipsychotic treatment in schizophrenia patients and investigated their associations with multiple candidate genes. We analyzed 60 genes encoding molecules of neurotransmission systems related to the pharmacological actions of antipsychotics (DRD2, HTR2A, ADRA2A, HRH2, etc.) and central and peripheral obesity-related pathways (LEP, NPY, POMC, GHRL, etc.) and genes known to be associated with obesity or BMI in recent GWASs (FTO, SEC16B, SH2B1, MC4R, etc.) ([Table 2]). We observed that rs696217 in GHRL showed suggestive evidence of association with both phenotypes. Although the associations did not withstand corrections for multiple testing, it appears to be meaningful that patients with the GG genotype showed not only a higher increase in BMI in one patient group but also a higher degree of appetite increase in an independent patient group. Given that AIWG is known to be associated with increased food intake, it is hardly surprising that genetic effects would be consistent across the 2 measures. The present finding suggests that the GHRL polymorphism might be involved in susceptibility to appetite stimulation during antipsychotic treatment in schizophrenia patients, which could result in weight gain. We also found an association with uncorrected P<0.05 in several SNPs of other candidate genes for only one phenotype.

Ghrelin is an endogenous ligand for the growth hormone-secretagogue receptor and is mainly secreted by the stomach in response to fasting. It mediates the perception of hunger or appetite for meal initiation via receptors in the hypothalamus [15] [16]. Clinical and animal data indicated that antipsychotic treatments modulate circulating ghrelin levels, and some studies have suggested that altered ghrelin signaling might contribute to an increase in food intake and weight gain during antipsychotic treatment [17] [18]. However, there has been no pharmacogenetic study reporting an association between the ghrelin gene, GHRL and AIWG. Ujike et al. investigated the association between rs696217 in GHRL and weight gain cross-sectionally measured in schizophrenia patients receiving olanzapine for 8–24 weeks but yielded negative result [9]. In the present study, using a mixed model analysis for repeated measures adjusting for confounding factors, we detected a difference in the increase rate of BMI over the 8-week treatment between genotypes of rs696217 ([Fig. 1a]). To the best of our knowledge, this is the first report of the association between GHRL and AIWG.

rs696217 (Leu72Met polymorphism) in GHRL is located outside the region of the mature ghrelin product, and its functional significance remains unclear [19]. However, it may alter mRNA stability or induce changes in protein processing, thus modifying ghrelin secretion or activity. This SNP has been studied intensively in obesity-related phenotypes, but the findings have been controversial. The Met72+genotype (GT or TT genotype, the protective genotypes of the present study) has been reported to be associated with the early onset of obesity in 3 studies [19] [20] [21]. However, it showed a protective effect against fat accumulation in a large population study of 3 cohorts [22] and type 2 diabetes in a recent meta-analysis [23]. According to a monozygotic twin study, the Met allele was more common among twin pairs with a low intra-pair BMI difference than those with a high intra-pair difference [24]. This suggested that carriers of the Leu72Leu genotype (GG genotype in the present study) are associated with variability in body weight in response to environmental factors, which is consistent with the results of the present study.

Among SNPs with uncorrected P<0.05 in the present study, rs1800544 in ADRA2A has been studied in several pharmacogenetic studies for AIWG, but data regarding the association between this SNP and AIWG have been conflicting. The G allele has been reported to have a protective effect against AIWG in the European American [25] and Malaysian population [26], but it has been shown to be associated with more weight gain in clozapine-treated Chinese [27] and olanzapine-treated Korean patients [28]. In our study, patients with the GG genotype of rs1800544 exhibited a lower increase rate in BMI than those with the GC/CC genotype (uncorrected P=0.003, the second lowest P-value) ([Fig. 1b]). However, the reason for such discrepancies remains unclear. In addition, we observed that patients with TT genotype of rs6311 in HTR2A had higher weight gain than those with CT/CC genotype (uncorrected P=0.006, the third lowest P-value) ([Fig. 1c]). The CC genotype of rs6311 was associated with lower weight gain compared to the TT genotype in risperidone-treated Chinese [29] and olanzapine-treated Japanese patients with CC genotype of rs6311 showed a significantly lower weight gain than those without it [9]. Taken together, these findings suggest that carrying the Tallele of rs6311 might be a genetic risk factor for AIWG. Besides above-mentioned genes, we found SNPs with uncorrected P<0.05 in other candidate genes including NEGR1, SEC16B, ADRA2B, DRD1, NTRK2, DRD2, GRIN2B, COMT, POMC, GRM3, DRD4, and CHRNA3. Among these genes, only DRD2 [30] [31] and DRD4 [32] have previous reports of association with AIWG, and all of the other genes do not have any previous evidence of association with AIWG. This study has some methodological limitations to be acknowledged. First, as the overall sample size was small, this study was only powered to detect susceptible SNPs with large effect size. The power analysis for the present study estimated that the power of the analyses for SNPs with small effect size (<0.1) or small MAF (<0.2) would be at low level (<0.6) (Supplementary Fig. 1). Second, there was a difference in the time of measuring weight gain and appetite change. Body weight changes were monitored during the early phase of antipsychotic treatment, but appetite changes were later measured during the maintenance period. Third, because appetite and eating-behavior changes were retrospectively measured, some recall bias might have affected the results. Fourth, although we adjusted for type of antipsychotic medications by statistical methods, there is the possibility that different propensities to induce weight gain among different antipsychotic medications might affect the results. Fifth, we could not analyze SNPs in the X-chromosome genes and whole tag SNPs in the relatively large-sized genes. Finally, we limited our analysis to individual SNP association. Further studies are required to identify gene-gene interaction among various candidate genes.

Considering the small sample size and no significant finding after correction for multiple testing, the results of the current study should be interpreted as preliminary findings. We observed trends of association between several SNPs, including rs696217 in GHRL, rs1800544 in ADRA2A and rs6311 in HTR2A, and AIWG. Interestingly, by adopting appetite and eating-behavior changes as intermediate phenotypes for pharmacogenetic study on AIWG, the current study provides suggestive evidence that GHRL might play a role in the pathogenesis of AIWG via appetite regulation. Thus, further studies with a larger sample size and analyses of the interaction effect with other genes are warranted to clarify the specific role of GHRL on AIWG.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

This study was supported by the Samsung Biomedical Research Institute grant (SMO1131991) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2012R1A3A2026438).

• References

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Correspondence

• 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
  Search in Google Scholar
• 2 Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004; 65 (Suppl. 18) 13-26
  PubMedSearch in Google Scholar
• 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
  PubMedSearch in Google Scholar
• 4 Muller DJ, Kennedy JL. Genetics of antipsychotic treatment emergent weight gain in schizophrenia. Pharmacogenomics 2006; 7: 863-887
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 10 McIntyre RS, Mancini DA, Basile VS. Mechanisms of antipsychotic-induced weight gain. J Clin Psychiatry 2001; 62 (Suppl. 23) 23-29
  PubMedSearch in Google Scholar
• 11 Baptista T, ElFakih Y, Uzcategui E et al. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 2008; 22: 477-495
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 18 Zhang Q, Deng C, Huang XF. The role of ghrelin signalling in second-generation antipsychotic-induced weight gain. Psychoneuroendocrinology 2013; 38: 2423-2438
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 29 Lane HY, Liu YC, Huang CL et al. Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006; 26: 128-134
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