Center for Biomarker Research and Personalized Medicine, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mol Psychiatry. 2011 Jan;16(1):76-85. doi: 10.1038/mp.2009.89. Epub 2009 Sep 1.
Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.
精神分裂症是一种经常造成严重破坏的神经精神疾病。了解影响抗精神病药物反应的遗传变异对于开发新的诊断测试以将个体精神分裂症患者与最有效和安全的药物相匹配非常重要。在这项研究中，我们使用全基因组方法来检测个体对奥氮平、喹硫平、利培酮、齐拉西酮和奋乃静治疗反应差异的遗传变异。我们的样本包括 738 名符合 DSM-IV 精神分裂症标准的患者，他们参加了临床抗精神病药物干预效果试验。使用 Affymetrix 500 K 基因分型平台和定制的 164 K 芯片对受试者进行基因分型，以提高全基因组覆盖率。使用阳性和阴性症状量表测量治疗效果。我们全基因组显著性的标准是一个预先指定的阈值，该阈值确保平均只有 10%的显著发现是虚假发现。达到我们预先指定阈值的最高统计结果涉及染色体 4p15 上基因间区域的单个核苷酸多态性 (SNP)。此外，ANK 重复和无菌α基序域包含蛋白 1B (ANKS1B) 基因和接触蛋白相关蛋白样 5 基因 (CNTNAP5) 中的 SNP 与奥氮平和利培酮对阴性症状的影响有关，非常接近我们宣布显著性的阈值。在 CNTNAP5 中最显著的 SNP 是非同义的，导致氨基酸取代。除了突出我们的主要结果外，我们还提供了所有 P 值供下载，以供有必要样本进行复制的研究人员使用。这项研究表明全基因组关联研究有可能发现介导抗精神病药物作用的新基因，这最终可能有助于将药物治疗针对精神分裂症患者进行个体化。
