title: Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain.
abstract: BACKGROUND
  Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.
  
  
  OBJECTIVE
  To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.
  
  
  METHODS
  Pharmacogenetic association study.
  
  
  METHODS
  The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial.
  
  
  METHODS
  The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects.
  
  
  METHODS
  Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.
  
  
  METHODS
  We conducted a genomewide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain.
  
  
  RESULTS
  Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P<10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P=5.59 X 10 (-12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels.
  
  
  CONCLUSIONS
  These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.
authors.affiliation: Psychiatry Research, Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004, USA. malhotra@lij.edu
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
authors.forename: Nabilah I
authors.initials: NI
authors.lastname: Chowdhury
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.forename: W Wolfgang
authors.initials: WW
authors.lastname: Fleischhacker
authors.forename: Rene S
authors.initials: RS
authors.lastname: Kahn
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: Todd
authors.initials: T
authors.lastname: Lencz
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000293:Adolescent; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D009765:Obesity / Q000139:chemically induced* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D008055:Lipids; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4