Association of Allelic Variation in Genes Mediating Aspects of Energy Homeostasis with Weight Gain during Administration of Antipsychotic Drugs (CATIE Study)

Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
Frontiers in Genetics 09/2011; 2(56). DOI: 10.3389/fgene.2011.00056
Source: PubMed


Antipsychotic drugs are widely used in treating schizophrenia, bipolar disorder, and other psychiatric disorders. Many of these drugs, despite their therapeutic advantages, substantially increase body weight. We assessed the association of alleles of 31 genes implicated in body weight regulation with weight gain among patients being treated with specific antipsychotic medications in the clinical antipsychotic trials in intervention effectiveness study, we found that rs2237988 in Potassium Channel Inwardly Rectifying Subfamily J Member 11 (KCNJ11), rs13269119 in Solute carrier family 30 member 8 (SLC30A8), and rs9922047 in fat mass and obesity associated (FTO) were associated with percent weight gain. We also observed the significant interaction of rs11643744 by treatment effect on the weight gain.

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    • "The important and independent Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial of the relative effects of several antipsychotic drugs35) is a valuable sample source for pharmacogenetic studies. A recent study of this cohort also identified an association of weight gain with a SNP in FTO, as well as with two other significant genes.36) "
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    ABSTRACT: Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.
    Clinical Psychopharmacology and Neuroscience 08/2012; 10(2):71-7. DOI:10.9758/cpn.2012.10.2.71
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    ABSTRACT: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. A recent study showed that a polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene is associated with antipsychotic-induced weight gain. The authors determined whether this association held true for weight gain after clozapine treatment. Thirty-two Chinese Han patients with first-episode schizophrenia were genotyped for the -759C/T polymorphism and had weight changes monitored after 6 weeks of clozapine treatment. The authors found that the 10 patients with the -759T variant allele showed significantly less weight gain than those without this allele. The effect was strongest in the male patients and not apparent in the female patients. These findings identify an important genetic factor associated with clozapine-induced weight increases in schizophrenia.
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    ABSTRACT: Psychotropic drugs are widely prescribed in Parkinson's disease (PD) without regard to their pathobiological effects, and these drugs affect the transcription of a large number of genes. Effects of these drugs on PD risk gene transcription were therefore surveyed. Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression evident in published data for 70 genes linked to PD risk. Psychotropic drugs can meaningfully affect PD risk gene mRNA transcription, including antipsychotics (upregulate dopamine receptors D2 and D3 (DRD2, DRD3); downregulate low-density lipoprotein receptor-related protein 8 (LRP8), ubiquitin carboxyl-terminal esterase L1 (UCHL1, also known as PARK5)), haloperidol (upregulates DRD3, parkin (PRKN, also known as PARK2), DRD2; downregulates brain-derived neurotrophic factor (BDNF)), risperidone (upregulates monoamine oxidase B (MAOB), DRD2), olanzapine (upregulates transmembrane protein 163 (TMEM163), BDNF, glutathione S-transferase mu 1 (GSTM1), MAOB, DRD2, solute carrier organic anion transporter family, member 3A1 (SLCO3A1)), aripiprazole (upregulates DRD2), quetiapine, paliperidone, lurasidone, carbamazepine, and many antidepressants (upregulate BDNF), lithium and bupropion (downregulate BDNF), amitriptyline (upregulates DRD3, DRD2), imipramine (upregulates BDNF, DRD3, DRD2), desipramine (upregulates BDNF, DRD3), and fluoxetine (upregulates acid beta-glucosidase (GBA), coiled-coil domain containing 62 (CCDC62), BDNF, DRD3, UCHL1, unc-13 homolog B (UNC13B), and perhaps huntingtin interacting protein 1 related (HIP1R); downregulates microtubule-associated protein tau (MAPT), methylcrotonoyl-coenzyme A carboxylase I (MCCC1), GSTM1, 28kDa calbindin 1 (CALB1)). Fluoxetine effects on BDNF and UCHL1 in GEO Profiles were statistically robust. This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on PD-relevant genes. Antipsychotics and serotoninergic antidepressants may potentially attenuate PD risk, and lithium and bupropion may augment risk, through MAPT, GBA, CCDC62, HIP1R, BDNF, and DRD2 transcription, with MAPT, GBA, and CCDC62 being strongly associated with PD risk in recent meta-analyses. Limitations of these findings and a research agenda to better relate them to the nigrostriatum and PD are discussed.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2012; 38(2):107-15. DOI:10.1016/j.pnpbp.2012.03.011 · 3.69 Impact Factor
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