Rare variants and biological pathways identified in treatment-refractory depression.,Journal of Neuroscience Research

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Rare variants and biological pathways identified in treatment-refractory depression.
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-03-03 , DOI: 10.1002/jnr.24609
Lora Lee McClain ₁ , Patricia Shaw ₂ , Roisin Sabol ₁ , Anna Maria Chedia _{2,

3} , Anna Maria Segretti ₁ , Manivel Rengasamy ₁ , David N Finegold ₄ , Lisa Pan ₁ , David Gerard Peters _{2,

4,

5}

Affiliation

Individuals diagnosed with major depressive disorder not responding to at least two adequate treatments are defined as treatment-refractory major depressive disorder (TR-MDD). Some TR-MDD patients have altered metabolic phenotypes that may be pharmacologically reversed. The characterization of these phenotypes and their underlying etiologies is paramount, particularly their genetic components. In this study, TR-MDD patients (n = 124) were recruited and metabolites were quantified in their cerebrospinal fluid (CSF) and peripheral blood. Three sub-categories of deficiencies were examined, namely 5-methyltetrahydrofolte (in CSF; n = 13), tetrahydrobiopterin (in CSF; n = 11), and abnormal acylcarnitine profiles (in peripheral blood; n = 8). Whole exome sequencing was performed on genomic DNA from the entire TR-MDD cohort and exonic variant allele frequencies for cases were compared to a control cohort (1:5 matching on ancestry). Low frequency, damaging alleles were identified and used for in silico pathway analyses. Three association signals for TR-MDD approached genome-wide significance on chromosomes 22, 7, and 3. Three risk-associated variants from a prior depression study were replicated. Relevant biological pathways were identified that contained an enrichment of rare, damaging variants in central nervous system (CNS)-specific pathways, including neurotransmitter receptors, potassium channels, and synapse transmission. Some TR-MDD patients had rare variants in genes that were previously associated with other psychiatric disorders, psychiatric endophenotypes, CNS structural defects, and CNS-related cellular and molecular functions. Exome analysis of metabolically phenotyped TR-MDD patients has identified potentially functional gene pathways and low frequency, deleterious gene variants for further investigation. Further studies in larger cohorts of biochemically phenotyped TR-MDD patients are desirable to extend and confirm these findings.

中文翻译：

在难治性抑郁症中发现的罕见变异和生物学途径。

被诊断患有重度抑郁症且对至少两种适当治疗没有反应的个体被定义为治疗难治性重度抑郁症（TR-MDD）。一些 TR-MDD 患者的代谢表型发生了改变，这些改变可以通过药物逆转。这些表型及其潜在病因的表征至关重要，特别是它们的遗传成分。在这项研究中，招募了 TR-MDD 患者 (n = 124)，并对他们的脑脊液 (CSF) 和外周血中的代谢物进行了定量。检查了三个子类别的缺陷，即 5-甲基四氢叶酸（CSF 中；n = 13）、四氢生物蝶呤（CSF 中；n = 11）和异常酰基肉碱谱（外周血中；n = 8）。对整个 TR-MDD 队列的基因组 DNA 进行全外显子组测序，并将病例的外显子变异等位基因频率与对照队列进行比较（血统 1:5 匹配）。低频、破坏性等位基因被识别并用于计算机途径分析。 TR-MDD 的三个关联信号在 22、7 和 3 号染色体上接近全基因组显着性。复制了先前抑郁症研究中的三个风险相关变异。相关的生物途径被确定，其中包含丰富的中枢神经系统（CNS）特异性途径中罕见的、破坏性的变异，包括神经递质受体、钾通道和突触传递。一些 TR-MDD 患者存在罕见的基因变异，这些变异以前与其他精神疾病、精神内表型、中枢神经系统结构缺陷以及中枢神经系统相关的细胞和分子功能有关。对代谢表型 TR-MDD 患者的外显子组分析已经确定了潜在的功能基因途径和低频有害基因变异，以供进一步研究。需要对更多生化表型 TR-MDD 患者进行进一步研究，以扩展和证实这些发现。

更新日期：2020-03-03

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