title: Genetics of second-generation antipsychotic and mood stabilizer-induced weight gain in bipolar disorder: common and specific effects of key regulators of fat-mass homoeostasis genes.
abstract: OBJECTIVE
  Second-generation antipsychotics (SGAP) and mood stabilizers (MS) are prescribed widely for the treatment of bipolar disorder, but they are associated with the risk of relevant side-effects, among which is weight gain. The identification of genes that predispose to weight gain would represent a useful tool to evaluate the risk-benefit ratio of treatment.
  
  
  METHODS
  This study investigated the genetic factors associated with weight gain in bipolar patients treated with SGAP, MS and their combinations (n=486). Single-nucleotide polymorphisms belonging to 16 candidate genes supported by the literature were investigated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) genome-wide dataset. Linear regression models were constructed including age, sex, initial weight and prescription of SGAP at high risk for inducing weight gain (olanzapine or clozapine) as covariates. Genes harbouring single-nucleotide polymorphisms associated with phenotypes were investigated by a pathway analysis.
  
  
  RESULTS
  No association was found between phenotypes and individual polymorphisms or pathways after multiple-test correction. HTR2C, LEP, FTO and TBC1D1 represented the top genes for weight gain during treatment with a SGAP and/or MS. A genome-wide signal (FTO rs9930506) associated previously with obesity was associated with psychotropic-induced weight gain. The genes that influenced both SGAP and MS weight gain were FTO, TBC1D1, MTHFR and HRH1. ADCY9, ADCY5 and PRKAG2 were interesting candidate genes that emerged from the pathway analysis.
  
  
  CONCLUSIONS
  This study was the first to compare the genes involved in SGAP-induced and MS-induced weight gain. Individual genes probably play a limited role in psychotropic-induced weight gain; further studies should focus on the extension from known candidate genes to wider groups of molecular pathways.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Creta
authors.forename: Chiara
authors.initials: C
authors.lastname: Fabbri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Serretti
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003024:Clozapine / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide; D011619:Psychotropic Drugs / Q000009:adverse effects; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D011619:Psychotropic Drugs; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine