Genome-wide association study of antipsychotic-induced QTc interval prolongation

被引：64

作者：

Aberg, K. ^{[1
]}

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

Liu, Y. ^{[2
,3
,4
]}

McClay, J. L. ^{[1
]}

Bukszar, J. ^{[1
]}

Jia, P. ^{[5
,6
,7
]}

Zhao, Z. ^{[5
,6
,7
]}

Perkins, D. ^{[3
]}

Stroup, T. S. ^{[8
]}

Lieberman, J. A. ^{[8
]}

Sullivan, P. F. ^{[2
,3
,4
,9
]}

van den Oord, E. J. C. G. ^{[1
]}

机构：

[1] Virginia Commonwealth Univ, Med Coll Virginia, Sch Pharm, Ctr Biomarker Res & Personalized Med, Richmond, VA 23298 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

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

[4] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[5] Vanderbilt Univ, Dept Biomed Informat, Med Ctr, Nashville, TN USA

[6] Vanderbilt Univ, Dept Psychiat, Med Ctr, Nashville, TN USA

[7] Vanderbilt Univ, Dept Canc Biol, Med Ctr, Nashville, TN USA

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

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

来源：

PHARMACOGENOMICS JOURNAL | 2012年 / 12卷 / 02期

关键词：

candidate gene analysis; genome-wide association study; schizophrenia; adverse effects; CATIE; COMMON GENETIC VARIANT; NOS1 REGULATOR NOS1AP; TORSADE-DE-POINTES; CARDIAC REPOLARIZATION; DRUGS; IDENTIFICATION; SCHIZOPHRENIA; DURATION; CATIE; RISK;

D O I：

10.1038/tpj.2010.76

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values = 1.45 x 10(-05) and 2.66 x 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value = 1.54 x 10(-7), Q-value = 0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation. The Pharmacogenomics Journal (2012) 12, 165-172; doi: 10.1038/tpj.2010.76; published online 5 October 2010

引用

页码：165 / 172

页数：8

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