Department of Psychiatry, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China.
Medical Laboratory Center, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China.
Bipolar Disord. 2018 Jun;20(4):370-380. doi: 10.1111/bdi.12580. Epub 2017 Dec 27.
Genome-wide association studies (GWASs) are used to identify genetic variants for association with bipolar disorder (BD) risk; however, each GWAS can only reveal a small fraction of this association. This study systematically analyzed multiple GWAS data sets to provide further insights into potential causal BD processes by integrating the results of Psychiatric Genomics Consortium Phase I (PGC-I) for BD with core human pathways and functional networks.
The i-Gsea4GwasV2 program was used to analyze data from the PGC-I GWAS for BD (the pathways came from Reactome), as well as the nominally significant pathways. We established a gene network of the significant pathways and performed a gene set analysis for each gene cluster of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) GWAS data for the volumes of the intracranial region and seven subcortical regions.
A total of 30 of 1816 Reactome pathways were identified and showed associations with BD risk. We further revealed 22 interconnected functional and topologically interacting clusters (Clusters 0-21) that were associated with BD risk. Moreover, we obtained brain transcriptome data from BrainSpan and found significant associations between common variants of the genes in Cluster 1 with the hippocampus (HIP; P = .026; family-wise error [FWE] correction) and amygdala (AMY; P = .016; FEW correction) in Cluster 8 with HIP (P = .022; FWE correction). The genes in Cluster 1 were enriched for the transcriptional co-expression profile in the prenatal AMY, and core genes (CDH4, MTA2, RBBP4, and HDAC2) were identified to be involved in regulating early brain development.
This study demonstrated that the HIP and AMY play a central role in neurodevelopment and BD risk.
全基因组关联研究（GWAS）用于鉴定与双相情感障碍（BD）风险相关的遗传变异；然而，每个 GWAS 只能揭示其中的一小部分关联。本研究系统地分析了多个 GWAS 数据集，通过整合精神疾病基因组学联盟第一阶段（PGC-I）的 BD 结果与核心人类途径和功能网络，提供了对潜在因果 BD 过程的进一步见解。
使用 i-Gsea4GwasV2 程序分析来自 PGC-I GWAS 的 BD 数据（途径来自 Reactome）以及名义上显著的途径。我们建立了一个显著途径的基因网络，并对增强神经影像学遗传学通过荟萃分析（ENIGMA）GWAS 数据的颅内区域和七个皮质下区域体积的每个基因簇进行基因集分析。
共鉴定出 1816 个 Reactome 途径中的 30 个与 BD 风险相关。我们进一步揭示了 22 个相互连接的功能和拓扑相互作用的簇（簇 0-21），它们与 BD 风险相关。此外，我们从 BrainSpan 获得了大脑转录组数据，并发现簇 1 中的基因常见变异与 HIP（P=0.026；FWE 校正）和 AMY（P=0.016；FEW 校正）以及簇 8 中的 HIP（P=0.022；FWE 校正）之间存在显著关联。簇 1 中的基因与产前 AMY 的转录共表达谱富集，核心基因（CDH4、MTA2、RBBP4 和 HDAC2）被鉴定为参与调节早期大脑发育。
本研究表明 HIP 和 AMY 在神经发育和 BD 风险中起核心作用。
