Data_Sheet_1_Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder.zip

BackgroundThe retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD.
MethodsA total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein–protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway.
ResultsOur analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress.
ConclusionThese results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

背景：逆行内源性大麻素（endocannabinoid, eCB）通路在病理生理学与遗传学层面均与重性抑郁障碍（major depressive disorder, MDD）的病因学密切相关。本研究旨在探究汉族重性抑郁障碍患者体内eCB通路遗传变异的潜在作用及其潜在机制。
方法：本研究共纳入96例初治首发重性抑郁障碍患者与62例健康对照（healthy controls, HCs）。通过全外显子组测序明确重性抑郁障碍患者的基因突变谱，对测序结果进行筛选，聚焦于与抑郁表型相关的低频变异及罕见突变（次要等位基因频率<0.05）。针对筛选出的146个基因开展富集分析，以明确富集程度最高的通路；同时构建蛋白质-蛋白质相互作用（protein-protein interaction, PPI）网络，探究eCB通路的生物学功能；最后结合现有文献开展初步分析，以探索遗传变异对该通路功能的影响。
结果：相较于健康对照，本研究在重性抑郁障碍患者体内共检出146个（15.02%）抑郁相关遗传突变，其中37个突变富集于逆行eCB信号通路。eCB通路内的7个枢纽基因与线粒体功能密切相关，包括复合体I相关基因（NDUFS4、NDUFV2、NDUFA2、NDUFA12、NDUFB11）以及参与调控线粒体氧化应激的蛋白（PARK7）与酶（DLD）功能相关基因。
结论：上述结果表明，逆行eCB通路的遗传突变可能是与重性抑郁障碍发病机制相关的潜在病因因素。