Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

被引：114

作者：

Adkins, D. E. ^{[1
]}

Aberg, K.

McClay, J. L.

Bukszar, J.

Zhao, Z. ^{[2
]}

Jia, P. ^{[2
]}

Stroup, T. S. ^{[3
]}

Perkins, D. ^{[3
]}

McEvoy, J. P. ^{[4
]}

Lieberman, J. A. ^{[5
]}

Sullivan, P. F. ^{[6
,7
]}

van den Oord, E. J. C. G.

机构：

[1] Virginia Commonwealth Univ, Dept Psychiat, Sch Pharm, Coll Med,Ctr Biomarker Res & Personalized Med, Richmond, VA 23223 USA

[2] Vanderbilt Univ, Med Ctr, Dept Biomed Informat Psychiat & Canc Biol, Nashville, TN USA

[3] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA

[4] Duke Univ, Dept Psychiat, Durham, NC 27706 USA

[5] Columbia Univ, Dept Psychiat, New York, NY USA

[6] Univ N Carolina, Dept Genet Psychiat & Epidemiol, Chapel Hill, NC USA

[7] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

来源：

MOLECULAR PSYCHIATRY | 2011年 / 16卷 / 03期

关键词：

genomewide association; antipsychotics; pharmacogenomics; personalized medicine; metabolic side effects; FALSE DISCOVERY RATE; CATIE SCHIZOPHRENIA TRIAL; DEPENDENT PROTEIN-KINASE; RII-BETA-SUBUNIT; WIDE ASSOCIATION; TARDIVE-DYSKINESIA; REGULATORY SUBUNIT; CANDIDATE GENE; DISEASE; EXPRESSION;

D O I：

10.1038/mp.2010.14

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (q = 0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q = 0.055). 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. Molecular Psychiatry (2011) 16, 321-332; doi:10.1038/mp.2010.14; published online 2 March 2010

引用

页码：321 / 332

页数：12

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