Genetic Determinants of Antidepressant Response

抗抑郁反应的遗传决定因素

• 批准号: 10266600
• 负责人: Francis J McMahon
• 金额: $ 49.59万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266600
• 关键词: Adverse effects; Adverse event; Alleles; Antidepressive Agents; Biological; Biological Factors; Candidate Disease Gene; Cellular Morphology; Code; Collaborations; Copy Number Polymorphism; Data; Disease remission; Family Study; Funding; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Markers; Genome; Genomics; Genotype; Goals; Growth and Development function; Heritability; High-Throughput Nucleotide Sequencing; Human; Individual; Ketamine; Learning; Light; Major Depressive Disorder; Mental Depression; Meta-Analysis; Methods; Michigan; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Mental Health; Neurons; Open Reading Frames; Outcome; Outcome Study; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Play; Recovery; Resistance; Risk; Role; Sampling; Scopolamine; Series; Symptoms; Techniques; Testing; Time; Treatment outcome; Twin Studies; United States National Institutes of Health; Untranslated RNA; Variant; Withdrawal; Work; alternative treatment; anxiety treatment; cell growth regulation; clinical center; cost; data harmonization; database of Genotypes and Phenotypes; effective therapy; exome; exome sequencing; experimental study; genetic testing; genetic variant; genome wide association study; genome-wide; improved; individual variation; induced pluripotent stem cell; insight; mortality; novel; patient response; personalized approach; programs; response; side effect; social factors; stem cells; synaptic function; therapy resistant; treatment duration; treatment response; treatment-resistant depression

NCT00088699 Strong evidence from family and twin studies demonstrates that major depressive disorder (MDD) is heritable, yet there has been limited progress in identifying the actual genes involved. A separate, perhaps overlapping set of genes is expected to play a role in individual variation in treatment response in MDD. By use of a variety of genetic tests, we seek to characterize patients who differ in their response to standard antidepressant treatments. In the first years of this project, candidate gene studies implicated a few genes in treatment outcome and other genes in adverse effects. We also participated in a meta-analysis of three genome-wide association studies of antidepressant outcome. Despite greater power of this combined sample to uncover association with common genetic markers, no genome-wide significant associations were found. We concluded that no common alleles of large effect on antidepressant outcome exist in these samples. Starting in 2018 we re-examined this question in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample using newer analysis methods that improve upon older genotyping techniques initially used in this sample. We carried out a new genome wide association study of antidepressant response in the STAR*D sample. This identified several SNPs associated with outcome after 12 weeks of treatment. Heritability was greater for outcomes following longer treatment periods, an unexpected finding that suggests the shorter treatment durations typically used in pharmacogenomic studies may not be optimal. Ongoing work is aimed at replicating these findings in additional samples. We are also using new, high-throughput sequencing methods to test for rarer genetic variants that may exert larger effects, at least in patients with treatment resistant depression (TRD). Sequencing of the coding regions of the genome (exome) has now been completed on over 250 treatment-resistant (TRD) or "typically responsive" patients drawn from the STAR*D, the Univ. Michigan Depression Center, and NIMH studies of novel antidepressants such as ketamine and scopolamine. Some of the exome sequencing was carried out at the NIH Intramural Sequencing Center with funds provided by the NIH Clinical Center Genomics Opportunity (CCGO) program, which also provided exome sequence from about 200 non-psychiatric patients for comparison. Of the 350,000 high-quality genetic variants identified, about 15,000 were found to be rare, potentially-damaging variants within the protein-coding regions of genes. No variant, gene, or gene set was found to be significantly associated with TRD after correction for multiple testing. To increase power, we have now received, through dbGAP, publicly available exome data from 2500 individuals with no known TRD. Analyses are underway to harmonize the data and carry out exome-wide gene burden analyses. In the coming year, additional work will be needed to evaluate any contribution of copy number variants or variants in non-coding regions. In collaboration with Carlos Zarate and colleagues, and with the help of the NHLBI Stem Cell Core, we have recently undertaken a series of studies aimed at characterizing the impact of antidepressant medication on gene expression and cellular morphology in human neurons derived from induced pluripotent stem cells. Early results from experiments with a metabolite of ketamine suggest that the drug changes expression of a large number of genes. Impacted genes are not random, but are instead enriched for pathways involved in regulation of cellular growth and development. In the coming year, additional work will examine the impact of ketamine and other antidepressants on electrical activity and synaptic function in cultured neurons. Taken together, these approaches may increase power and identify genes and biological pathways robustly associated with resistance to anti-depressant treatment. Such genes could provide important clues about how to develop more effective antidepressant therapies.

NCT00088699 来自家庭和双胞胎研究的有力证据表明，主要的抑郁症（MDD）是可遗传的，但是在识别实际基因方面的进展有限。预计一组单独的，也许重叠的基因将在MDD中的治疗反应中的个体变异中发挥作用。通过使用各种基因检测，我们试图表征他们对标准抗抑郁治疗反应不同的患者。 在该项目的头几年，候选基因研究暗示了一些基因在治疗结果和其他基因中受到不利影响。我们还参与了三项全基因组抗抑郁结果研究的荟萃分析。尽管该组合样品对发现与普通遗传标记的关联的功率更大，但未发现全基因组的显着关联。我们得出的结论是，在这些样品中，没有对抗抑郁结果产生巨大影响的共同等位基因。 从2018年开始，我们使用较新的分析方法在测序的治疗替代方法中重新检查了该问题，以减轻抑郁症（星*D）样品，这些方法可以改进该样品中最初使用的较旧基因分型技术。我们对Star*d样品中的抗抑郁反应进行了一项新的基因组范围的关联研究。这确定了在治疗12周后与结果相关的几个SNP。在更长的治疗期之后的结局中，遗传力更大，这一意外发现表明，在药物基因组学研究中通常使用的较短治疗持续时间可能不是最佳的。正在进行的工作旨在在其他样本中复制这些发现。 我们还使用了新的高通量测序方法来测试稀有的遗传变异，至少在耐药抑郁症（TRD）的患者中可能发挥更大的影响。基因组（Exome）的编码区域的测序现已在250多个耐治疗（TRD）或“通常反应敏感的”患者上完成，该患者是从Univ的Star*D中汲取的。密歇根抑郁症中心以及NIMH对新型抗抑郁药（如氯胺酮和scopolamine）的研究。一些外显子组测序是在NIH壁内测序中心进行的，由NIH临床中心基因组学机会（CCGO）计划提供的资金，该计划还提供了来自约200名非精神病患者的外显子组序列，以进行比较。在鉴定出的350,000个高质量遗传变异中，发现大约15,000个在基因的蛋白质编码区域内是罕见的，潜在的破坏性变体。多次测试后，没有发现未发现变异，基因或基因集与TRD显着相关。为了增加功率，我们现在通过DBGAP收到了来自2500名尚无trd的人的公开可用的外来数据。正在进行分析以协调数据并进行外显域基因负担分析。在来年，将需要额外的工作来评估非编码区域中拷贝数变体或变体的任何贡献。 与Carlos Zarate及其同事合作，并在NHLBI干细胞核心的帮助下，我们最近进行了一系列研究，旨在表征抗抑郁药对从诱导的多能干细胞产生的人类神经元中抗抑郁药对基因表达和细胞形态的影响。氯胺酮代谢产物实验的早期结果表明，药物会改变大量基因的表达。受影响的基因不是随机的，而是在与细胞生长和发育的调节有关的途径中富集。在来年，额外的工作将检查氯胺酮和其他抗抑郁药对培养神经元中电活动和突触功能的影响。 综上所述，这些方法可能会增加功率，并确定与抗抑制剂治疗的耐药性牢固相关的基因和生物学途径。这样的基因可以提供有关如何开发更有效的抗抑郁疗法的重要线索。