Peters Eric J, Slager Susan L, Jenkins Greg D, Reinalda Megan S, Garriock Holly A, Shyn Stanley I, Kraft Jeffrey B, McGrath Patrick J, Hamilton Steven P
Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, CA, USA.
Pharmacogenet Genomics. 2009 Jan;19(1):1-10. doi: 10.1097/FPC.0b013e3283163ecd.
Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STARD) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STARD sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.
已有多篇报告发表，研究血清素相关候选基因的常见变异与抗抑郁反应之间的关系，而大多数结果都模棱两可。我们之前曾报道血清素相关基因的变异与选择性血清素再摄取抑制剂氟西汀的反应之间存在显著关联。在此，我们试图通过以下方式扩展并复制这些结果：（i）对我们用氟西汀治疗的样本中五个血清素相关候选基因（HTR1A、HTR2A、TPH1、TPH2和MAOA）的外显子和假定调控区域进行重测序，以发现新的变异；（ii）从重测序数据中为这些基因选择标签单核苷酸多态性（SNP）；以及（iii）在参与缓解抑郁症的序贯治疗替代方案（STARD）临床研究的独立样本（N = 1953）中，评估这些标签SNP与选择性血清素再摄取抑制剂西酞普兰反应的关联性。在STARD样本集中，未发现之前与氟西汀反应相关的任何变异与西酞普兰反应相关。也未发现任何其他标签SNP与西酞普兰反应相关。我们还对HTR2A中的另一个SNP（rs7997012）进行了基因分型，该SNP之前曾报道与该样本中西酞普兰治疗的结果相关，但未被我们研究的任何其他SNP很好地标记，它与西酞普兰反应相关（P = 0.0002），有力地支持了在同一STAR*D样本中的先前观察结果。我们的结果表明，对血清素相关基因进行重测序并未发现任何之前未被识别的额外常见SNP。这五个基因的遗传变异似乎对西酞普兰反应的影响很小，尽管之前观察到的关联得到了支持，有待在独立样本中进行复制。
