Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

D. E. Adkins, K. Åberg, J. L. McClay, J. Bukszár, Z. Zhao, P. Jia, T. S. Stroup, D. Perkins, Joseph Patrick McEvoy, J. A. Lieberman, P. F. Sullivan, E. J.C.G. Van Den Oord

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.

Original languageEnglish (US)
Pages (from-to)321-332
Number of pages12
JournalMolecular Psychiatry
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Antipsychotic Agents
Single Nucleotide Polymorphism
Risperidone
Homeobox Genes
Schizophrenia
Validation Studies
Waist Circumference
Individuality
Blood Glucose
Hip
Hemoglobins
Heart Rate
Pharmacogenomic Testing
Clinical Trials
Blood Pressure
Lipids
Weights and Measures
Therapeutics
Research
Genes

Keywords

  • antipsychotics
  • genomewide association
  • metabolic side effects
  • personalized medicine
  • pharmacogenomics

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Adkins, D. E., Åberg, K., McClay, J. L., Bukszár, J., Zhao, Z., Jia, P., ... Van Den Oord, E. J. C. G. (2011). Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Molecular Psychiatry, 16(3), 321-332. https://doi.org/10.1038/mp.2010.14

Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. / Adkins, D. E.; Åberg, K.; McClay, J. L.; Bukszár, J.; Zhao, Z.; Jia, P.; Stroup, T. S.; Perkins, D.; McEvoy, Joseph Patrick; Lieberman, J. A.; Sullivan, P. F.; Van Den Oord, E. J.C.G.

In: Molecular Psychiatry, Vol. 16, No. 3, 01.03.2011, p. 321-332.

Research output: Contribution to journalArticle

Adkins, DE, Åberg, K, McClay, JL, Bukszár, J, Zhao, Z, Jia, P, Stroup, TS, Perkins, D, McEvoy, JP, Lieberman, JA, Sullivan, PF & Van Den Oord, EJCG 2011, 'Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs', Molecular Psychiatry, vol. 16, no. 3, pp. 321-332. https://doi.org/10.1038/mp.2010.14
Adkins DE, Åberg K, McClay JL, Bukszár J, Zhao Z, Jia P et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Molecular Psychiatry. 2011 Mar 1;16(3):321-332. https://doi.org/10.1038/mp.2010.14
Adkins, D. E. ; Åberg, K. ; McClay, J. L. ; Bukszár, J. ; Zhao, Z. ; Jia, P. ; Stroup, T. S. ; Perkins, D. ; McEvoy, Joseph Patrick ; Lieberman, J. A. ; Sullivan, P. F. ; Van Den Oord, E. J.C.G. / Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. In: Molecular Psychiatry. 2011 ; Vol. 16, No. 3. pp. 321-332.
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