title: Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients.
abstract: Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG.We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates.In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (P(corrected) = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (P(corrected) = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (P(corrected) = 0.011).Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.
authors.affiliation: Neurogenetics Section, Neuroscience Department, Centre forAddiction and Mental Health & Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Brandl
authors.forename: Caroline
authors.initials: C
authors.lastname: Weber
authors.forename: Olga
authors.initials: O
authors.lastname: Likhodi
authors.forename: Clement C
authors.initials: CC
authors.lastname: Zai
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Hahn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D016009:Chi-Square Distribution; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000235:genetics*; D009518:New York / Q000453:epidemiology; D009820:Ohio / Q000453:epidemiology; D000077152:Olanzapine; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia / Q000188:drug therapy* / Q000208:ethnology; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C571130:CNR1 protein, human; D009478:Neuropeptide Y; D043884:Receptor, Cannabinoid, CB1; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine