Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Department of Prevention and Health Care, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Neurosci Lett. 2024 Sep 14;839:137935. doi: 10.1016/j.neulet.2024.137935. Epub 2024 Aug 14.
Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through "vast but mixed" Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS.
We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0).
TWAS identified 362 genes with P value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (P=1.07 × 10), ALOX5AP (P=3.12 × 10), and PLEC (P=1.27 × 10). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (P=0.0020, P=0.0000), TMPRSS9 (P=0.0405, P=0.0032), and SNX10 (P=0.0104, P=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species.
We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.
双相情感障碍（BD）是一种使人虚弱的神经精神疾病，它与通过“广泛但混杂”的全基因组关联研究（GWAS）的遗传变异有关。转录组全基因组关联研究（TWAS）在解释影响复杂疾病的遗传因素方面更为有效，并且可以更可靠地帮助识别风险基因。因此，本研究旨在通过 TWAS 分析鉴定具有 TWAS 的扩展 BD 家系中的潜在 BD 风险基因。
我们对来自精神疾病基因组学联盟（PGC）的扩展 BD 家系进行了 TWAS 分析和表达数量性状基因座（eQTL）分析，并使用了 BD 全基因组关联研究（GWAS）汇总数据。此外，通过来自基因表达综合数据库（GEO）数据集（GSE23848 和 GSE46416）的 mRNA 表达谱验证了 TWAS 鉴定的 BD 相关基因。使用 RStudio（版本 4.2.0）进行功能富集和注释分析。
TWAS 鉴定出 362 个 P 值<0.05 的基因，经过 Bonferroni 校正后仍有 18 个基因具有统计学意义，例如 SEMA3G（P=1.07×10）、ALOX5AP（P=3.12×10）和 PLEC（P=1.27×10）。进一步的整合分析检测到 6 个重叠基因，例如 UQCRB（P=0.0020，P=0.0000）、TMPRSS9（P=0.0405，P=0.0032）和 SNX10（P=0.0104，P=0.0015）。使用 TWAS 鉴定的基因进行基因本体论（GO）富集分析鉴定出 40 个显著的 GO 术语，例如线粒体 ATP 合成偶联电子传递、线粒体呼吸、需氧电子传递链、氧化磷酸化、线粒体膜蛋白和泛醌活性。京都基因与基因组百科全书（KEGG）途径富集分析确定了 15 个与 BD 相关的途径，例如氧化磷酸化、内源性大麻素信号、神经退行性变和活性氧物质。
我们发现了一组与 BD 相关的基因和途径，验证了神经发育异常、炎症反应和线粒体功能障碍在 BD 病理中的重要作用，为理解 BD 的遗传基础提供了新的信息。
