Koga Arthur T, Strauss John, Zai Clement, Remington Gary, De Luca Vincenzo
Department of Psychiatry, University of Toronto, Toronto, Canada.
Universidade Federal de Ouro Preto, UFOP, Ouro Preto, Minas Gerais, Brazil.
J Neural Transm (Vienna). 2016 Mar;123(3):329-38. doi: 10.1007/s00702-015-1472-7. Epub 2016 Jan 28.
In recent years, several studies have investigated genetic polymorphisms of antipsychotic drug-metabolizing enzymes and receptors. However, most studies focused on drug response and very few have investigated the genetic influence on antipsychotic dosage. The aim of the present study is to test the association between antipsychotic dosages at genome-wide level. The current dosage of antipsychotic medications was collected from 79 schizophrenia patients. The dosage was standardized using three different methods: chlorpromazine equivalent (CPZe), defined daily dose (DDD), and percentage of maximum dose (PM %). The patients were then genotyped using the Illumina HumanOmni2.5-8 BeadChip Kit. All markers were screened for significance using linear regression, and the p values were visualized using a Manhattan plot. The genome-wide analysis showed that the top Single-Nucleotide Polymorphisms (SNPs) associated with dosage variation were rs981975 on chromosome 14 for CPZe, rs4470690 on chromosome 4 for PM %, and rs79323383 on chromosome 8 for DDD. However, no genome-wide significantly associated SNPs were identified. In this pilot sample, we found promising trends for pharmacodynamic targets associated with antipsychotic dosage. Therefore, studies combining large prescription databases may identify genetic predictors to adjust the dose of antipsychotic medication.
近年来，多项研究调查了抗精神病药物代谢酶和受体的基因多态性。然而，大多数研究集中在药物反应上，很少有研究调查基因对抗精神病药物剂量的影响。本研究的目的是在全基因组水平上测试抗精神病药物剂量之间的关联。收集了79例精神分裂症患者目前使用的抗精神病药物剂量。使用三种不同方法对剂量进行标准化：氯丙嗪等效剂量（CPZe）、限定日剂量（DDD）和最大剂量百分比（PM%）。然后使用Illumina HumanOmni2.5 - 8 BeadChip试剂盒对患者进行基因分型。使用线性回归筛选所有标记的显著性，并使用曼哈顿图可视化p值。全基因组分析表明，与剂量变化相关的顶级单核苷酸多态性（SNP）分别为：CPZe对应14号染色体上的rs981975，PM%对应4号染色体上的rs4470690，DDD对应8号染色体上的rs79323383。然而，未发现全基因组显著相关的SNP。在这个试点样本中，我们发现了与抗精神病药物剂量相关的药效学靶点的有前景的趋势。因此，结合大型处方数据库的研究可能会确定调整抗精神病药物剂量的基因预测指标。
