A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping
A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping
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DOI：
10.1038/s41398-020-0738-5
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发表时间：
2020-02-03
影响因子：
6.8
通讯作者：
Serretti, Alessandro
中科院分区：
文献类型：
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作者：
Fabbri, Chiara;Kasper, Siegfried;Serretti, Alessandro
难治性抑郁(TRD)发生在30%的重度抑郁障碍(MDD)患者中，但TRD的遗传学以前研究很少。对1209例MDD患者进行了全外显子组测序和全基因组基因分型。将抗抑郁药反应与对一种治疗无效和对两种或两种以上治疗无反应(TRD)进行比较。对携带破坏性变异的风险进行了差异测试。计算表示基因和途径中变异负担的分数，根据每个变异的功能(特征)分数和频率加权每个变异。在70%的样本(训练)中使用基于基因和基于途径的评分来建立TRD和无反应的预测模型，其中70%的样本(训练)在剩余30%的样本(测试)中进行测试，还评估了增加的临床预测因素。使用基于Exome阵列的数据在STAR*D和GENDEP中测试了独立复制。与应答者相比，TRD和无应答者携带破坏性变体的风险并不高。与TRD相关的基因/途径包括那些调节细胞生存和增殖、神经退化和免疫反应的基因/途径。遗传模型显示了TRD与疗效的显著预测，并通过添加临床预测因子而得到改善，但它们并不比单独使用临床预测因子显著更好。复制结果是由临床因素驱动的，除了在接受5-羟色胺能抗抑郁药物治疗的受试者中开发的一个模型，该模型显示在STAR*D遗传分数分布的极端情况下预测明显改善。这些结果表明TRD涉及相关的生物学机制，并为预测TRD提供了一种新的方法。
Treatment-resistant depression (TRD) occurs in 30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.