| 摘要 | 双相情感障碍（Bipolar Disorder, BD）是一种常见的精神类疾病，发病率为1% ~ 2%。研究表明，该病具有复杂的遗传结构，遗传度在80%到85%之间。目前已经有大量双相情感障碍相关的遗传学研究发表，并积累了从单核苷酸多态性（Single Nucleotide Polymorphism, SNP）、基因、拷贝数变异（Copy Number Variation, CNV）到染色体区域的丰富数据。同时，该病经常与精神分裂症（Schizophrenia, SZ）和重度抑郁症（Major Depressive Disorder, MDD）具有一些相似的临床特征，研究表明三种疾病之间共享一定的遗传因素。然而，这些研究结果散落在不同的文献研究中，且结果之间存在很大的不一致性，这为全面理解双相情感障碍的遗传学研究现状，进一步探索疾病致病机理和遗传机制带来了很大的不便。为了深入研究双相情感障碍的遗传基础及其与高相关疾病的共享机制，我们开发了双相情感障碍遗传学数据库-BDgene。该数据库可以通过http://bdgene.psych.ac.cn访问。 通过仔细的文献筛选与阅读，我们整合了来自800多篇文献的双相情感障碍遗传因子，涵盖了从SNP到染色体区域的多种类型，其中既包含阳性结果，也包含阴性结果。同时，为了探索双相情感障碍与精神分裂症和重度抑郁症共享的遗传机制，我们还整合了来自于双相情感障碍与其它两种疾病交叉研究的结果。基于这些文献数据，我们进一步地开展了一系列的生物信息学深入分析与挖掘，包括候选基因优先级排序、全基因组关联数据（GWAS）的基于通路分析、遗传位点的功能注释、疾病交叉分析及候选基因的功能富集分析。 最终，BDgene数据库共收集了与双相情感障碍相关的3304个SNPs、824个基因、41个基因-基因相互作用对及789个染色体区域，其中部分遗传因子为双相情感障碍与精神分裂症和重度抑郁症所共享。进一步地，通过深入的生物信息学分析，我们共得到了43个BD高优先级的核心基因、12个同时被连锁分析和CNV研究支持的BD候选基因、57个新的与BD相关的生物通路、126个BD-SZ及78个BD-MDD的共享基因。同时，通过对43个BD核心基因的功能富集分析，我们发现了突触传递、钙信号转导通路和突触后膜三个最具有统计显著性的与BD相关的生物通路，而共享基因的富集分析则进一步验证了生物节律紊乱可能是导致三种精神疾病的共同发生机制之一。综上所述，BDgene中所收集的文献来源数据为全面理解双相情感障碍的遗传学研究现状提供了广泛而可靠的数据集。同时，对遗传因子的完整注释及深入的扩展分析提供了一系列新的候选位点及其可能的作用通路，这些结果一方面为进一步的验证研究提供可靠候选，另一方面也为理解遗传因子的作用通路提供理论指导，从而最终解释双相情感障碍的遗传基础，促进疾病的诊断与治疗。 |
| 其他摘要 | Bipolar disorder (BD) is a common psychiatric disorder with prevalence of 1% ~2%. Studies have shown that the disease has a complex genetic structure, and its heritability is as high as 80% ~85%. Currently, a large number of genetic studies related to BD have been published and accumulated extensive genetic data, ranging from single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP), gene, copy number variations (Copy Number Variation, CNV) to chromosomal region. Meanwhile, several BD clinical features, including psychosis and suicidality, can also be observed in schizophrenia (SZ) and major depressive disorder (MDD). It indicates there might be potential shared genetic factors between these disorders. However, these findings are scattered in numerous publications with many inconsistencies. It brought great challenge to form a comprehensive understanding of the status of genetics studies, and to further explore the genetic mechanism and disease pathogenesis. In order to study the genetic basis of BD and its shared mechanism with SZ/MDD, we have developed a comprehensive genetic database-BDgene. BDgene is freely available at http://bdgene.psych.ac.cn. Through careful manual screening and reading, we integrated various types of genetic factors of BD, ranging from SNP to chromosome region, from more than 800 publications, with both positive and negative results. Meanwhile, in order to explore shared genetic mechanisms, we also integrated those results from cross-disorder studies of BD and SZ/MDD. Further, we conducted a series of in-depth data analysis and data mining based on the literature-origin data, including gene prioritization, pathway-based analysis, functional annotation of disease-related genetic factors, disease intersection analysis and pathway enrichment analysis. Finally, BDgene contained 3304 SNPs, 824 genes, 41 gene-gene interactions and 789 regions, some of which are shared with SZ and/or MDD. Besides, in-depth data analyses identified 43 BD core genes with high priority, 12 candidate genes supported by both linkage and CNV analysis, 70 new potential biological pathways, as well as 126 BD-SZ shared genes and 78 BD-MDD shared genes. Furthermore, three pathways, that is ‘synaptic transmission’, ‘calcium signaling pathway’ and ‘postsynaptic membrane’ were identified as the most statistically significant ones related to BD through pathway enrichment analysis on 43 BD core genes. In addition, pathway enrichment analysis on shared genes validated ‘circadian rhythm’ may be an important common pathway contributing to three disorders. In summary, literature-origin data collected in BDgene have provided an extensive and reliable dataset for a better understanding of current research status. In the mean time, full annotation and in-depth analysis of genetic factors have offered novel candidates and its potential pathways. These results would not only propose reliable candidates from further validation studies, but also provide theoretical guidance for the understanding of biological pathways involved by genetic factors, and ultimately help elucidate the genetic basis of BD, and promote diagnosis and treatment of the disease. |
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