PharmGScore scores of compound genetic variant burden for psychiatric treatment optimization
PharmGScore scores of compound genetic variant burden for psychiatric treatment optimization
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用于优化精神病治疗的复合遗传变异负担的 PharmGScore 评分
DOI：
10.1101/2023.06.27.23291888
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Borczyk M
中科院分区：
文献类型：
--
作者：
Borczyk M
抗抑郁药物的可接受性部分取决于遗传因素。参与抗抑郁反应的基因列表，包括药物不良反应（adr）是广泛的，包括药物代谢酶（药物基因）和参与药效学的基因。药物基因的变异传统上以星形等位基因的形式报道，并部分注释已知的表型后果。由于不可能分析所有的基因型-表型对，计算方法仍然是实用的解决方案。预测抗抑郁药物治疗反应的药理学框架将为患者提供巨大的好处。在这项研究中，我们提出了一个评分系统（PharmGScore）来评估多基因中罕见和常见的遗传变异负担。PharmGScore是通过规范化和聚合现有的、完善的计算变异预测因子（CADD、Fathmm-xf、provan、Mutation Assessor）来构建的。我们发现，该评分有效地将无功能和功能下降的药物遗传变异与PharmVar报告的正常和功能增加的药物遗传变异区分开来（PharmGScore AUC= 0.86）。与组成部分评分相比，PharmGScore的表现有所改善（auc: CADD= 0.79; FATHMM-XF= 0.81; provan = 0.81; Mutation Assessor= 0.75）。然后，我们将PharmGScore应用于UK Biobank （UKB）的200k外显子组序列。我们报告了在具有抗抑郁药物毒性诊断代码（T43）的组中，CYP2C19和CYP2C9基因PharmGScore高（> 50）和9个药物基因的化合物PharmGScore高（> 100）的UKB参与者的过度代表。2）. 然后我们分析所有接受任何抗抑郁药物毒性或不良反应诊断的UKB参与者（n= 602）。我们指出了高负荷基因可能与抗抑郁药物毒性或不良反应相关，并证实了CYP2C19和CYP2D6在这一过程中的已知作用。最后，我们发现在治疗过程中出现抗抑郁药物不良反应或意外中毒的患者具有更高的由9个细胞色素P450基因组成的PharmGScore。我们的研究提出了一种新的范式来评估外显子组测序数据中与抗抑郁反应相关的复合遗传变异负担。这种方法可以进一步应用于用户定义的一组基因来研究其他药理学特征。
The acceptability of antidepressant drugs partly depends on genetic factors. The list of genes involved in antidepressant response, including Adverse Drug Reactions (ADRs) is broad and contains both drug-metabolizing enzymes (pharmacogenes) and genes involved in pharmacodynamics. Variants in pharmacogenes are traditionally reported in the form of star alleles and are partially annotated with known phenotypic consequences. As it is unfeasible to analyze all genotype-phenotype pairs, computational approaches remain the practical solution. A pharmacogenetic framework to predict responses to antidepressant drug treatment would provide great benefit to patients. In this study, we present a scoring system (PharmGScore) to assess both rare and common genetic variant burden across multiple genes. The PharmGScore is constructed by normalizing and aggregating existing, well-established computational variant predictors (CADD, Fathmm-xf, PROVEAN, Mutation Assessor). We show that this score effectively distinguishes no and decreased function from normal and increased function pharmacogenetic variants reported in PharmVar (PharmGScore AUC= 0.86). PharmGScore has improved performance when compared to its component scores (AUCs: CADD= 0.79; FATHMM-XF= 0.81; PROVEAN= 0.81; Mutation Assessor= 0.75). We then apply the PharmGScore to the 200k exome sequences of the UK Biobank (UKB). We report the overrepresentation of UKB participants with high (> 50) gene PharmGScore for CYP2C19 and CYP2C9 and with high (> 100) compound PharmGScore from nine pharmacogenes within a group with an antidepressant toxicity diagnostic code (T43. 2). We then analyze all UKB participants that received any antidepressant toxicity or ADR diagnosis (n= 602). We indicate genes for which a higher burden may be associated with antidepressant toxicity or ADRs and confirm the known roles of CYP2C19 and CYP2D6 in this process. Finally, we show that patients who experienced ADRs to antidepressants in the therapeutic process or accidental poisoning with antidepressants have a higher PharmGScore composed of nine cytochrome P450 genes. Our study proposes a novel paradigm to assess the compound genetic variant burden associated with antidepressant response from exome sequencing data. This approach can be further applied to a user-defined set of genes to investigate other pharmacological traits.
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4.6
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作者：
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影响因子：
4.5
作者：
Pandi MT;Koromina M;Tsafaridis I;Patsilinakos S;Christoforou E;van der Spek PJ;Patrinos GP
通讯作者：
Patrinos GP
影响因子：
5.6
作者：
van Westrhenen R;van Schaik RHN;van Gelder T;Birkenhager TK;Bakker PR;Houwink EJF;Bet PM;Hoogendijk WJG;van Weelden-Hulshof MJM
通讯作者：
van Weelden-Hulshof MJM