High-throughput sequencing of the synaptome in major depressive disorder.
High-throughput sequencing of the synaptome in major depressive disorder.
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DOI：
10.1038/mp.2015.98
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发表时间：
2016-05
影响因子：
11
通讯作者：
Goes FS
中科院分区：
文献类型：
--
作者：
Pirooznia M;Wang T;Avramopoulos D;Potash JB;Zandi PP;Goes FS
严重抑郁障碍(MDD)是导致全球残疾的主要原因之一。尽管MDD具有显著的遗传性，但大规模的全基因组关联研究(GWAS)尚未确定与MDD密切相关的常见变异。尽管正在为下一波GWAS积累更大的样本量，但到目前为止，很少有研究专注于MDD研究中的罕见遗传变异。我们对之前通过蛋白质组学实验确定的1742个突触基因的外显子进行了测序。用PLINK/SEQ软件进行单变异体分析、基因负荷分析和基因集分析。GeneMANIA相互作用数据库用于识别基于蛋白质-蛋白质相互作用的网络。病例选自早发性、复发性抑郁症的家族性收集，并与筛查的对照组进行比较。经过广泛的质量控制，我们分析了259例家族性早发性MDD和334例对照。单变异分析和基因负荷分析的关联检验统计量的分布与零假设一致。然而，对优先基因集的分析显示，在所有测试的基因集和注释类别的校正中幸存下来的Cav2适配器基因集中的破坏性单个变种(优势比=2.6P=0.0008)存在显著的相关性(经验P=0.049)。此外，我们还发现了在涉及肌动蛋白聚合和树突棘形成的14个基因的基于蛋白质的网络中罕见变异丰富的统计显著证据(名义P=0.0031)。总之，我们已经确定了一个在MDD中过度表达的罕见变异的统计意义上的基因集和基因网络，为钙信号和树突调节可能参与抑郁症的病因提供了初步证据。
Major depressive disorder (MDD) is among the leading causes of worldwide disability. Despite its significant heritability, large-scale genome-wide association studies (GWASs) of MDD have yet to identify robustly associated common variants. Although increased sample sizes are being amassed for the next wave of GWAS, few studies have as yet focused on rare genetic variants in the study of MDD. We sequenced the exons of 1742 synaptic genes previously identified by proteomic experiments. PLINK/SEQ was used to perform single variant, gene burden and gene set analyses. The GeneMANIA interaction database was used to identify protein–protein interaction-based networks. Cases were selected from a familial collection of early-onset, recurrent depression and were compared with screened controls. After extensive quality control, we analyzed 259 cases with familial, early-onset MDD and 334 controls. The distribution of association test statistics for the single variant and gene burden analyses were consistent with the null hypothesis. However, analysis of prioritized gene sets showed a significant association with damaging singleton variants in a Cav2-adaptor gene set (odds ratio = 2.6; P = 0.0008) that survived correction for all gene sets and annotation categories tested (empirical P = 0.049). In addition, we also found statistically significant evidence for an enrichment of rare variants in a protein-based network of 14 genes involved in actin polymerization and dendritic spine formation (nominal P = 0.0031). In conclusion, we have identified a statistically significant gene set and gene network of rare variants that are over-represented in MDD, providing initial evidence that calcium signaling and dendrite regulation may be involved in the etiology of depression.