title: Association study of GABAA α2 receptor subunit gene variants in antipsychotic-associated weight gain.
abstract: Schizophrenia treatment has been hampered by undesirable adverse effects, including weight gain and associated complications. Recent candidate gene studies have been exploring the appetite regulation pathways in antipsychotic-associated weight gain (AAWG) with some promising leads. Genome-wide association studies of obesity have pointed to a number of potential candidate genes, such as MC4R, that were later found to be shared with AAWG. GABAA α2 receptor subunit (GABRA2) was another potential candidate gene for obesity from genome-wide association studies; however, it has not been explored in AAWG. We examined 9 single nucleotide polymorphisms across the GABRA2 gene. Prospective weight change was assessed for a total of 160 schizophrenia patients of European ancestry. The rs279858 marker was associated with percent weight change, with the patients homozygous for the TT genotype experiencing higher percentage weight gain on average than the C allele carriers (P = 0.009). When we performed the analysis considering each clinical site using a meta-analytic method, the results remained statistically significant (P = 1.4e-4). These findings became even more significant when we considered only patients taking clozapine or olanzapine, the 2 medications with higher risk for weight gain (P < 1e-10). GABRA2 genetic variants may play a role in predicting AAWG. However, replication in larger and independent samples is required.
authors.affiliation: From the *Neurogenetics Section, Centre for Addiction and Mental Health; †Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; ‡Department of Psychiatry and Psychotherapy, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany; §Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York Presbyterian Hospital & Columbia University Medical Center, New York, NY; and ║Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Clement C H
authors.initials: CC
authors.lastname: Zai
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Nabilah I
authors.initials: NI
authors.lastname: Chowdhury
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Brandl
authors.forename: Sajid A
authors.initials: SA
authors.lastname: Shaikh
authors.forename: Natalie
authors.initials: N
authors.lastname: Freeman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D011446:Prospective Studies; D021122:Protein Subunits / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; C484841:GABRA2 protein, human; D021122:Protein Subunits; D011963:Receptors, GABA-A