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Association study of GABAA α2 receptor subunit gene variants in antipsychotic-associated weight gain

Clement C H Zai1, Arun K Tiwari, Nabilah I Chowdhury

  • 1From 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.

Journal of Clinical Psychopharmacology
|December 17, 2014
PubMed

Insights

Genetic variations in the GABRA2 gene may predict antipsychotic-associated weight gain (AAWG) in schizophrenia patients. Specifically, the rs279858 marker showed a significant association with increased weight gain, particularly with clozapine and olanzapine use.

Area of Science:

  • Pharmacogenetics
  • Neuroscience
  • Psychiatry

Background:

  • Antipsychotic-associated weight gain (AAWG) is a significant adverse effect in schizophrenia treatment.
  • Appetite regulation pathways are being investigated as potential contributors to AAWG.
  • Genome-wide association studies have identified candidate genes for obesity, some overlapping with AAWG.

Purpose of the Study:

  • To investigate the role of the GABAA α2 receptor subunit (GABRA2) gene in antipsychotic-associated weight gain (AAWG).
  • To examine the association between specific GABRA2 single nucleotide polymorphisms (SNPs) and weight changes in schizophrenia patients.

Main Methods:

  • Genotyping of 9 single nucleotide polymorphisms (SNPs) across the GABRA2 gene.
  • Prospective assessment of weight change in 160 schizophrenia patients of European ancestry.
  • Meta-analysis of results across clinical sites and stratified analysis for clozapine/olanzapine users.

Main Results:

  • The rs279858 marker in the GABRA2 gene was significantly associated with percent weight change (P = 0.009).
  • Patients with the TT genotype at rs279858 showed higher average weight gain compared to C allele carriers.
  • The association remained significant after meta-analysis across sites (P = 1.4e-4) and was particularly strong in patients taking clozapine or olanzapine (P < 1e-10).

Conclusions:

  • Genetic variants within the GABRA2 gene may serve as predictors for antipsychotic-associated weight gain (AAWG).
  • Further validation in larger, independent cohorts is necessary to confirm these findings.

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