title: Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis.
abstract: Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.forename: Todd
authors.initials: T
authors.lastname: Lencz
authors.affiliation: Department of Psychology and Neuroscience, Duke University, Durham, NY.
authors.forename: Ryan X
authors.initials: RX
authors.lastname: Zhang
authors.affiliation: Drug Development Division, Sumitomo Dainippon Pharma Co. Ltd, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nitta
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Maayan
authors.affiliation: Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health System, Glen Oaks, NY.|Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY.|Department of Mathematics, Hofstra University, Hempstead, NY.
authors.forename: Majnu
authors.initials: M
authors.lastname: John
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Robinson
authors.affiliation: Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: W Wolfgang
authors.initials: WW
authors.lastname: Fleischhacker
authors.affiliation: Department of Psychiatry, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Rene S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA.
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.affiliation: Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
mesh_terms: D014150:Antipsychotic Agents / Q000009:adverse effects*; D006801:Humans; D010597:Pharmacogenetics / Q000379:methods*; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000235:genetics*; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents
keywords: BMI; SNP; antipsychotics; meta-analysis; pharmacogenetics; weight gain