Myung W, Kim J, Lim S-W, Shim S, Won H-H, Kim Seonwoo, Kim Sangha, Lee M-S, Chang H S, Kim J-W, Carroll B J, Kim D K
Department of Psychiatry, Samsung Medical Center, Seoul, Korea.
Sungkyunkwan University School of Medicine, Seoul, Korea.
Transl Psychiatry. 2015 Sep 8;5(9):e633. doi: 10.1038/tp.2015.127.
We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.
我们在大多为成年期起病的非精神病性单相抑郁症未经治疗发作期的韩国患者这一民族同质样本中，开展了一项关于抗抑郁药物反应的三阶段全基因组关联研究（GWAS）。在病例选择、诊断、依从性核查及结局评估方面维持了严格的质量控制。分析的病例完成了6周治疗，血浆药物浓度充足。总体成功完成率为85.5%。在接受四种允许使用的选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药物之一治疗的481例患者的发现样本中（第1阶段），通过全基因组搜索在三条染色体上鉴定出四个候选单核苷酸多态性（SNP）。在一项对230例接受SSRI治疗患者的聚焦复制研究中，这四个SNP候选位点中的两个得到了确认（第2阶段）。对第1阶段和第2阶段样本合并分析（n = 711）显示，这两个处于完全连锁不平衡状态的SNP候选位点具有全基因组关联研究的显著性（P = 1.60×10⁻⁸）。在一项对159例接受非SSRI抗抑郁药物米氮平治疗患者的聚焦交叉复制研究中（第3阶段），这两个显著的SNP也得到了确认。对第1阶段、第2阶段和第3阶段样本合并分析（n = 870）也显示这两个SNP具有全基因组关联研究的显著性，在对性别、年龄、既往发作次数、起病年龄及基线严重程度进行校正后该显著性仍然存在（P = 3.57×10⁻⁸）。对于每个SNP，随着次要等位基因（无反应等位基因）数量的增加，反应率下降（优势比 = 0.31，95%置信区间：0.20 - 0.47）。与抗抑郁反应显著相关的两个SNP是位于7号染色体7q11.22区域的AUTS2基因的rs7785360和rs12698828。该基因与人类心理功能和神经行为障碍有多种已知的联系。建议在其他种族人群中进行严格的复制研究。
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