Martone Alfonso, Possidente Chiara, Fanelli Giuseppe, Fabbri Chiara, Serretti Alessandro
Department of Biomedical and Neuromotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur Arch Psychiatry Clin Neurosci. 2024 Aug 27. doi: 10.1007/s00406-024-01873-1.
Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.
重度抑郁症（MDD）的治疗反应和耐药性显示出显著的遗传成分，但由于MDD的异质性，先前的研究效力有限。这篇文献综述聚焦于与MDD治疗结果相关的遗传因素，探讨它们与临床相关症状维度相关因素的重叠情况。我们在PubMed上搜索了：（1）调查MDD疗效结果的全基因组关联研究（GWAS）或全外显子组测序研究（WES）；（2）研究MDD治疗结果与特定抑郁症状维度之间关联的研究；以及（3）已确定症状维度的GWAS。我们确定了13项MDD治疗结果的GWAS和1项WES，报告了几个参与基因表达、免疫系统调节、突触传递和可塑性、神经发生和分化的重要基因座、基因和基因集。九个症状维度与治疗效果不佳相关，并且先前的GWAS对其进行了研究（焦虑、神经质、快感缺失、认知功能、忧郁症、自杀企图、精神病、睡眠、社交能力）。有四个基因与治疗结果和这些症状维度均相关：CGREF1（焦虑）；MCHR1（神经质）；FTO和NRXN3（睡眠）。在考虑与治疗结果有暗示性关联的基因时，发现了其他重叠信号。尽管在基因或变异水平上没有重复，但治疗结果的遗传研究在生物学过程层面显示出趋同性。与感兴趣的症状维度重叠的遗传信号可能指向共同的生物学机制以及针对个体患者临床特征的新治疗潜在靶点。
