Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA; Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia.
Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Antioquia, Colombia.
J Affect Disord. 2021 Jan 15;279:491-500. doi: 10.1016/j.jad.2020.10.027. Epub 2020 Oct 17.
Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response.
Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes.
The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess.
Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted.
Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response.
ClinicalTrials.gov NCT00265291.
罕见的遗传功能变体可能导致与药物作用相关的基因的功能变异性的 30-40%。因此，我们研究了罕见功能变体在抗抑郁反应中的作用。
符合《精神疾病诊断与统计手册-IV》（DSM-IV）重度抑郁症（MDD）标准的墨西哥裔美国人参与了一项前瞻性随机、双盲研究，用去甲丙咪嗪或氟西汀治疗。使用全外显子组基因分型数据进行罕见变异分析。利用显著基因列表进行网络和途径分析。
Kernel-Based Adaptive Cluster 方法在 35 个与治疗缓解显著相关的基因中识别出功能罕见变体（错误发现率，FDR <0.01）。这些基因的途径分析支持以下基因本体过程的参与：嗅觉/感觉转导、对细胞因子刺激的反应调节，以及减数细胞周期过程。
我们的研究没有安慰剂组。我们无法将抗抑郁药血药浓度作为协变量。我们的研究仅基于 65 名墨西哥裔美国人的小样本量。需要进一步的研究使用更大的队列。
我们的数据确定了 MDD 患者抗抑郁药物反应中的几个罕见功能变体。这些可能成为预测药物反应的遗传标记。
ClinicalTrials.gov NCT00265291。
